U.S. patent number 10,351,549 [Application Number 15/747,220] was granted by the patent office on 2019-07-16 for amide derivatives having multimodal activity against pain.
This patent grant is currently assigned to LABORATORIOS DEL DR. ESTEVE S.A.. The grantee listed for this patent is ESTEVE PHARMACEUTICALS, S.A.. Invention is credited to Carmen Almansa-Rosales, Monica Garcia-Lopez.
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United States Patent |
10,351,549 |
Garcia-Lopez , et
al. |
July 16, 2019 |
**Please see images for:
( Certificate of Correction ) ** |
Amide derivatives having multimodal activity against pain
Abstract
The present invention relates to amide derivatives having dual
pharmacological activity towards both the sigma (.sigma.) receptor,
and the .mu.-opioid receptor, to processes of preparation of such
compounds, to pharmaceutical compositions comprising them, and to
their use in therapy, in particular for the treatment of pain.
Inventors: |
Garcia-Lopez; Monica
(Barcelona, ES), Almansa-Rosales; Carmen (Barcelona,
ES) |
Applicant: |
Name |
City |
State |
Country |
Type |
ESTEVE PHARMACEUTICALS, S.A. |
Barcelona |
N/A |
ES |
|
|
Assignee: |
LABORATORIOS DEL DR. ESTEVE
S.A. (Barcelona, ES)
|
Family
ID: |
54056149 |
Appl.
No.: |
15/747,220 |
Filed: |
July 28, 2016 |
PCT
Filed: |
July 28, 2016 |
PCT No.: |
PCT/EP2016/001309 |
371(c)(1),(2),(4) Date: |
January 24, 2018 |
PCT
Pub. No.: |
WO2017/016668 |
PCT
Pub. Date: |
February 02, 2017 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20180237415 A1 |
Aug 23, 2018 |
|
Foreign Application Priority Data
|
|
|
|
|
Jul 29, 2015 [EP] |
|
|
15382391 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
25/04 (20180101); C07D 487/04 (20130101); A61P
29/00 (20180101); C07D 211/56 (20130101); C07D
401/12 (20130101); C07B 2200/09 (20130101); C07B
2200/07 (20130101) |
Current International
Class: |
A61K
31/397 (20060101); A61K 31/4439 (20060101); A61P
25/04 (20060101); A61P 29/00 (20060101); C07D
205/04 (20060101); C07D 207/10 (20060101); C07D
401/12 (20060101); C07D 211/56 (20060101); A61K
31/4025 (20060101); A61K 31/40 (20060101); C07D
487/04 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2728588 |
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May 1978 |
|
DE |
|
0252670 |
|
Jun 1987 |
|
EP |
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WO 03/048154 |
|
Jun 2003 |
|
WO |
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WO 2006/021544 |
|
Mar 2006 |
|
WO |
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WO 2015/091939 |
|
Jun 2015 |
|
WO |
|
Other References
Bornot et al., J. Med. Chem, 2013, 56, 1197-1210. cited by
applicant .
Chien, et al., Neuroscience Letters, 1995, 190, 137-139. cited by
applicant .
Dickenson, et al., Eur J Pain 9, 113-116 (2005). cited by applicant
.
Goldberg, et al., BMC Public Health. 11, 770 (2011). cited by
applicant .
Mao, et al., J. Pain , 12, 157-166 (2011). cited by applicant .
Patel, et al., Bioorganic & Medicinal Chemistry Letters, 2008,
18, 5689-5693. cited by applicant .
Turk, et al., Lancet, 377, 2226-2235 (2011). cited by applicant
.
Zamanillo, et al., Eur. J. Pharmacoi, 716, 78-93 (2013). cited by
applicant .
International Search Report for PCT/EP2016/001309 dated Aug. 30,
2016. cited by applicant.
|
Primary Examiner: Coleman; Brenda L
Attorney, Agent or Firm: Hueschen and Sage
Claims
The invention claimed is:
1. A compound of Formula (I): ##STR00101## wherein m is 1 or 2; n
is 0, 1 or 2; p is 0, 1 or 2; X is a bond, --C(R.sub.xR.sub.x')--,
C.dbd.O or --O--; wherein R.sub.x is selected from the group
consisting of halogen, --OR.sub.8, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x' is
selected from the group consisting of hydrogen, halogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; R.sub.8 is selected from the group consisting of
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; W is nitrogen or carbon; R.sub.1 is selected
from the group consisting of substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; wherein the cycloalkyl, aryl or
heterocyclyl in R.sub.1, if substituted, is substituted with one or
more substituents selected from the group consisting of halogen,
--R.sub.11, --OR.sub.11, --NO.sub.2; NR.sub.11R.sub.11''',
NR.sub.11C(O)R.sub.11'--, --NR.sub.11S(O).sub.2R.sub.11',
--S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; and wherein the cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with ##STR00102## or .dbd.O; wherein the alkyl, alkenyl
or alkynyl in R.sub.1, if substituted, is substituted with one or
more substituent/s selected from the group consisting of
--OR.sub.11, halogen, --CN, haloalkyl, haloalkoxy, --SR.sub.11,
--S(O)R.sub.11, and --S(O).sub.2R.sub.11; wherein R.sub.11,
R.sub.11' and R.sub.11'' are independently selected from the group
consisting of hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from the group
consisting of hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; R.sub.2 is selected from the group consisting of
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.12,
--OR.sub.12--NO.sub.2--NR.sub.12R.sub.12''',
NR.sub.12C(O)R.sub.12', --NR.sub.12S(O).sub.2R.sub.12',
--S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; and wherein the cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with ##STR00103## or .dbd.O; wherein the alkyl, alkenyl
or alkynyl in R.sub.2, if substituted, is substituted with one or
more substituent/s selected from --OR.sub.12, halogen, --CN,
haloalkyl, haloalkoxy, --SR.sub.12, --S(O)R.sub.12, and
--S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12' and R.sub.12''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.12''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.3 is selected from
the group consisting of substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, --NR.sub.7R.sub.7' and
--CH.sub.2OR.sub.7; wherein R.sub.7 and R.sub.7' are independently
selected from the group consisting of hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.4 and R.sub.4' are independently selected from the
group consisting of hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-5 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl, R.sub.5 and
R.sub.5' are independently selected from the group consisting of
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; R.sub.6 and R.sub.6' are independently selected
from the group consisting of hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; and wherein
##STR00104## is selected from the group consisting of ##STR00105##
wherein Rn is selected from the group consisting of unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; wherein the alkyl, alkenyl or alkynyl, other
than those defined in R.sub.1 or R.sub.2, if substituted, is
substituted with one or more substituent/s selected from the group
consisting of --OR.sub.13, halogen, --CN, haloalkyl, haloalkoxy,
--SR.sub.13, --S(O)R.sub.13, and --S(O).sub.2R.sub.13; wherein
R.sub.13 is selected from the group consisting of hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and
unsubstituted C.sub.2-6 alkynyl; wherein the aryl, heterocyclyl or
cycloalkyl other than those defined in R.sub.1 or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from halogen, --R.sub.14, --OR.sub.14, --NO.sub.2,
--NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.2).sub.2OR.sub.14; and wherein the cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1 or
R.sub.2, if substituted, may also be substituted with ##STR00106##
or .dbd.O; wherein R.sub.14, R.sub.14'' and R.sub.14'' are
independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6, alkenyl, unsubstituted C.sub.2-6
alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and
unsubstituted heterocyclyl; and wherein R.sub.14''' is selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc:
optionally as a stereoisomer, including enantiomers and
diastereomers, a racemate or a mixture of at least two
stereoisomers, including enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof.
2. The compound according to claim 1, wherein ##STR00107## W is
nitrogen or carbon; and Rn is selected from unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl.
3. The compound according to claim 2, wherein W is nitrogen and Rn
is unsubstituted C.sub.1-6 alkyl.
4. The compound according to claim 1, wherein the compound is a
compound of formula (I') ##STR00108##
5. The compound according to claim 1, wherein X is a bond or
--O.
6. The compound according to claim 5, wherein X is a bond; and/or m
is 1; and/or n is 0; and/or p is 0.
7. The compound according to claim 1, wherein the compound is a
compound of Formula (I.sup.2') ##STR00109## wherein X is a bond,
C.dbd.O or --O--; m is 1 or 2; and p is 0, 1 or 2.
8. The compound according to claim 7, wherein X is a bond; m is 1;
and p is 0.
9. The compound according to claim 1, wherein the compound is a
compound of Formula (I.sup.3') ##STR00110##
10. The compound according to claim 1, wherein R.sub.1 is selected
from the group consisting of substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl.
11. The compound according to claim 10, wherein R.sub.1 is
substituted or unsubstituted phenyl or substituted or unsubstituted
pyridine.
12. The compound according to claim 1, wherein R.sub.2 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, and
substituted or unsubstituted aryl.
13. The compound according to claim 12, wherein R.sub.2 is
substituted or unsubstituted phenyl.
14. The compound according claim 1, wherein R.sub.3 is substituted
or unsubstituted C.sub.1-6 alkyl.
15. The compound according to claim 14, wherein R.sub.3 is
unsubstituted ethyl.
16. The compound according to claim 1, wherein R.sub.4 and R.sub.4'
are independently selected from hydrogen and substituted or
unsubstituted C.sub.1-6 alkyl.
17. The compound according to claim 1, wherein R.sub.5 and R.sub.5'
are independently selected from hydrogen and substituted or
unsubstituted C.sub.1-6 alkyl.
18. The compound according to claim 17, wherein R.sub.5 and
R.sub.5' are both hydrogen.
19. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(3-fluoropyridin-2--
yl)propionamide
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylpropionamide
(S)--N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylpropiona-
mide
(R)--N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylprop-
ionamide optionally as a stereoisomer, including enantiomers and
diastereomers, a racemate or a mixture of at least two
stereoisomers, including enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof.
20. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl-
)pyridin-2-yl)propionamide Enantiomer of
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl-
)pyridin-2-yl)propionamide
N-(2-(3-(benzyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluoromethyl)p-
yridin-2-yl)propionamide
N-(2-(3-(isobutyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluoromethyl-
)pyridin-2-yl)propionamide
N-(2-(3-((2-methoxyethyl)(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluo-
romethyl)pyridin-2-yl)propionamide
N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluorometh-
yl)pyridin-2-yl)propionamide Enantiomer of
N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluorometh-
yl)pyridin-2-yl)propionamide
N-(2-(3-((2-ethoxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(triflu-
oromethyl)pyridin-2-yl)propionamide Enantiomer of
N-(2-(3-((2-ethoxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(triflu-
oromethyl)pyridin-2-yl)propionamide optionally as a stereoisomer,
including enantiomers and diastereomers, a racemate or a mixture of
at least two stereoisomers, including enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof.
21. A process for the preparation of the compound of Formula (I) as
defined in claim 1, wherein the process comprises reacting a
compound of Formula VII ##STR00111## with a compound of formula
Villa through an alkylaton reaction or VIIIb through a reductive
amination reaction ##STR00112## or wherein the process comprises an
acylation of a compound of Formula IVb ##STR00113## wherein Y is
##STR00114## with a compound of formula Va or Vb ##STR00115##
wherein ##STR00116## is selected from the group consisting of
##STR00117## wherein L is a leaving group selected from the group
consisting of halogen, mesylate, tosylate and triflate, and wherein
Z is chloro, bromo, hydroxy, methoxy or ethoxy.
22. A process for the preparation of a compound of Formula (I)
according to claim 1, employing a compound of Formula IIa, IIb,
III, IVa, IVb, Va, Vb, VI, VII, VIIIa or VIIIb ##STR00118##
##STR00119## wherein ##STR00120## is selected from the group
consisting of ##STR00121## wherein L is a leaving group selected
from the group consisting of halogen, mesylate, tosylate and
triflate, wherein Z is chloro, bromo, hydroxy, methoxy or ethoxy;
wherein Y is ##STR00122## and wherein PG is a protecting group
selected from the group consisting of benzyl and
tert-butoxycarbonyl.
23. A pharmaceutical composition which comprises the compound
according to claim 1, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier, adjuvant or
vehicle.
24. A method of treating pain in a subject in need thereof,
comprising administration of an effective amount of the compound
according to claim 1.
25. The method according to claim 24, wherein the pain is selected
from the group consisting of medium to severe pain, visceral pain,
chronic pain, cancer pain, migraine, inflammatory pain, acute pain,
neuropathic pain, allodynia, and hyperalgesia.
Description
FIELD OF THE INVENTION
The present invention relates to amide derivatives having dual
pharmacological activity towards both the sigma (.sigma.) receptor,
and the .mu.-opioid receptor (MOR or mu-opioid receptor), to
pharmaceutical compositions comprising them, and to their use in
therapy, in particular for the treatment of pain.
BACKGROUND OF THE INVENTION
The adequate management of pain constitutes an important challenge,
since currently available treatments provide in many cases only
modest improvements, leaving many patients unrelieved [Turk D C,
Wilson H D, Cahana A. Treatment of chronic non-cancer pain. Lancet
377, 2226-2235 (2011)]. Pain affects a big portion of the
population with an estimated prevalence of around 20% and its
incidence, particularly in the case of chronic pain, is increasing
due to the population ageing. Additionally, pain is clearly related
to comorbidities, such as depression, anxiety and insomnia, which
lead to important productivity losses and socio-economical burden
[Goldberg D S, McGee S J. Pain as a global public health priority.
BMC Public Health. 11, 770 (2011)]. Existing pain therapies include
non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists,
calcium channel blockers and antidepressants, but they are much
less than optimal regarding their safety ratio. All of them show
limited efficacy and a range of secondary effects that preclude
their use, especially in chronic settings.
As mentioned before, there are few available therapeutic classes
for the treatment of pain, and opioids are among the most
effective, especially when addressing severe pain states. They act
through three different types of opioid receptors (mu, kappa and
gamma) which are transmembrane G-protein coupled receptors (GPCRs).
Still, the main analgesic action is attributed to the activation of
the .mu.-opioid receptor (MOR). However, the general administration
of MOR agonists is limited due to their important side effects,
such as constipation, respiratory depression, tolerance, emesis and
physical dependence [Meldrum, M. L. (Ed.). Opioids and Pain Relief:
A Historical Perspective. Progress in Pain Research and Management,
Vol 25. IASP Press, Seattle, 2003]. Additionally, MOR agonists are
not optimal for the treatment of chronic pain as indicated by the
diminished effectiveness of morphine against chronic pain
conditions. This is especially proven for the chronic pain
condidtions of neuropathic or inflammatory origin, in comparison to
its high potency against acute pain. The finding that chronic pain
can lead to MOR down-regulation may offer a molecular basis for the
relative lack of efficacy of morphine in long-term treatment
settings [Dickenson, A. H., Suzuki, R. Opioids in neuropathic pain:
Clues from animal studies. Eur J Pain 9, 113-6 (2005)]. Moreover,
prolonged treatment with morphine may result in tolerance to its
analgesic effects, most likely due to treatment-induced MOR
down-regulation, internalization and other regulatory mechanisms.
As a consequence, long-term treatment can result in substantial
increases in dosing in order to maintain a clinically satisfactory
pain relief, but the narrow therapeutic window of MOR agonists
finally results in unacceptable side effects and poor patient
compliance.
The sigma-1 (.sigma..sub.1) receptor was discovered 35 years ago
and initially assigned to a new subtype of the opioid family, but
later on and based on the studies of the enantiomers of SKF-10,047,
its independent nature was established. The first link of the
.sigma..sub.1 receptor to analgesia was established by Chien and
Pasternak [Chien C C, Pasternak G W. Sigma antagonists potentiate
opioid analgesia in rats. Neurosci. Lett. 190, 137-9 (1995)], who
described it as an endogenous anti-opioid system, based on the
finding that .sigma..sub.1 receptor agonists counteracted opioid
receptor mediated analgesia, while .sigma..sub.1 receptor
antagonists, such as haloperidol, potentiated it.
Many additional preclinical evidences have indicated a clear role
of the .sigma..sub.1 receptor in the treatment of pain [Zamanillo
D, Romero L, Merlos M, Vela J M. Sigma 1 receptor: A new
therapeutic target for pain. Eur. J. Pharmacol, 716, 78-93 (2013)].
The development of the .sigma..sub.1 receptor knockout mice, which
show no obvious phenotype and perceive normally sensory stimuli,
was a key milestone in this endeavour. In physiological conditions
the responses of the .sigma..sub.1 receptor knockout mice to
mechanical and thermal stimuli were found to be undistinguishable
from WT ones but they were shown to possess a much higher
resistance to develop pain behaviours than WT mice when
hypersensitivity entered into play. Hence, in the .sigma..sub.1
receptor knockout mice capsaicin did not induce mechanical
hypersensitivity, both phases of formalin-induced pain were
reduced, and cold and mechanical hypersensitivity were strongly
attenuated after partial sciatic nerve ligation or after treatment
with paclitaxel, which are models of neuropathic pain. Many of
these actions were confirmed by the use of .sigma..sub.1 receptor
antagonists and led to the advancement of one compound, S1RA, into
clinical trials for the treatment of different pain states.
Compound S1RA exerted a substantial reduction of neuropathic pain
and anhedonic state following nerve injury (i.e., neuropathic pain
conditions) and, as demonstrated in an operant self-administration
model, the nerve-injured mice, but not sham-operated mice, acquired
the operant responding to obtain it (presumably to get pain
relief), indicating that .sigma..sub.1 receptor antagonism relieves
neuropathic pain and also address some of the comorbidities (i.e.,
anhedonia, a core symptom in depression) related to pain
states.
Pain is multimodal in nature, since in nearly all pain states
several mediators, signaling pathways and molecular mechanisms are
implicated. Consequently, monomodal therapies fail to provide
complete pain relief. Currently, combining existing therapies is a
common clinical practice and many efforts are directed to assess
the best combination of available drugs in clinical studies [Mao J,
Gold M S, Backonja M. Combination drug therapy for chronic pain: a
call for more clinical studies. J. Pain 12, 157-166 (2011)]. Hence,
there is an urgent need for innovative therapeutics to address this
unmet medical need.
As mentioned previously, opioids are among the most potent
analgesics but they are also responsible for various adverse
effects which seriously limit their use.
Accordingly, there is still a need to find compounds that have an
alternative or improved pharmacological activity in the treatment
of pain, being both effective and showing the desired selectivity,
and having good "drugability" properties, i.e. good pharmaceutical
properties related to administration, distribution, metabolism and
excretion.
Thus, the technical problem can therefore be formulated as finding
compounds that have an alternative or improved pharmacological
activity in the treatment of pain.
In view of the existing results of the currently available
therapies and clinical practices, the present invention offers a
solution by combining in a single compound binding to two different
receptors relevant for the treatment of pain. This was mainly
achieved by providing the compounds according to the invention that
bind both to the .mu.-opioid receptor and to the .sigma..sub.1
receptor.
SUMMARY OF THE INVENTION
In this invention a family of structurally distinct amide
derivatives which have a dual pharmacological activity towards both
the sigma (.sigma.) receptor, and the .mu.-opioid receptor was
identified thus solving the above problem of identifying
alternative or improved pain treatments by offering such dual
compounds.
The invention is in one aspect directed to a compound having a dual
activity binding to the .sigma..sub.1 receptor and the .mu.-opioid
receptor for use in the treatment of pain.
As this invention is aimed at providing a compound or a chemically
related series of compounds which act as dual ligands of the
.sigma..sub.1 receptor and the .mu.-opioid receptor it is a very
preferred embodiment if the compound has a binding expressed as
K.sub.i which is preferably <1000 nM for both receptors, more
preferably <500 nM, even more preferably <100 nM.
The invention is directed in a main aspect to a compound of general
Formula (I),
##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, W, m, n and p are as
defined below in the detailed description.
A further object of the invention refers to the processes for
preparation of compounds of general formula (I).
A still further object of the invention refers to the use of
intermediate compounds for the preparation of a compound of general
formula (I).
It is also an object of the invention a pharmaceutical composition
comprising a compound of formula (I).
Finally, it is an object of the invention the use of compound as a
medicament and more particularly for the treatment of pain and pain
related conditions.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to a family of structurally distinct
amide derivatives which have a dual pharmacological activity
towards both the sigma (.sigma.) receptor and the .mu.-opioid
receptor.
The invention is in one aspect directed to a compound having a dual
activity binding to the .sigma..sub.1 receptor and the .mu.-opioid
receptor for use in the treatment of pain.
As this invention is aimed at providing a compound or a chemically
related series of compounds which act as dual ligands of the
.sigma..sub.1 receptor and the .mu.-opioid receptor it is a
preferred embodiment if the compound has a binding expressed as
K.sub.i which is preferably <1000 nM for both receptors, more
preferably <500 nM, even more preferably <100 nM.
The applicant has surprisingly found that the problem on which the
present invention is based can be solved by using a multimodal
balanced analgesic approach combining two different synergistic
activities in a single drug (i.e., dual ligands which are
bifunctional and bind to .mu.-opioid receptor and to .sigma..sub.1
receptor), thereby enhancing the opioid analgesia through the
.sigma..sub.1 activation without increasing the undesirable side
effects. This supports the therapeutic value of a dual
MOR/.sigma..sub.1 receptor compound whereby the .sigma..sub.1
receptor binding component acts as an intrinsic adjuvant of the MOR
binding component.
This solution offered the advantage that the two mechanisms
complement each other in order to treat pain and chronic pain using
lower and better tolerated doses needed based on the potentiation
of analgesia but avoiding the adverse events of .mu.-opioid
receptor agonists.
A dual compound that possess binding to both the .mu.-opioid
receptor and to the .sigma..sub.1 receptor shows a highly valuable
therapeutic potential by achieving an outstanding analgesia
(enhanced in respect to the potency of the opioid component alone)
with a reduced side-effect profile (safety margin increased
compared to that of the opioid component alone) versus existing
opioid therapies.
Advantageously, the dual compounds according to the present
invention would in addition show one or more the following
functionalities: .sigma..sub.1 receptor antagonism and .mu.-opioid
receptor agonism. It has to be noted, though, that both
functionalities "antagonism" and "agonism" are also sub-divided in
their effect into subfunctionalities like partial agonism or
inverse agonism. Accordingly, the functionalities of the dual
compound should be considered within a relatively broad
bandwidth.
An antagonist blocks or dampens agonist-mediated responses. Known
subfunctionalities are neutral antagonists or inverse agonists.
An agonist increases the activity of the receptor above its basal
level. Known subfunctionalities are full agonists, or partial
agonists.
In addition, the two mechanisms complement each other since MOR
agonists are only marginally effective in the treatment of
neuropathic pain, while .sigma..sub.1 receptor antagonists show
outstanding effects in preclinical neuropathic pain models. Thus,
the .sigma..sub.1 receptor component adds unique analgesic actions
in opioid-resistant pain. Finally, the dual approach has clear
advantages over MOR agonists in the treatment of chronic pain as
lower and better tolerated doses would be needed based on the
potentiation of analgesia but not of the adverse events of MOR
agonists.
A further advantage of using designed multiple ligands is a lower
risk of drug-drug interactions compared to cocktails or
multi-component drugs, thus involving simpler pharmacokinetics and
less variability among patients. Additionally, this approach may
improve patient compliance and broaden the therapeutic application
in relation to monomechanistic drugs, by addressing more complex
aetiologies. It is also seen as a way of improving the R&D
output obtained using the "one drug-one target" approach, which has
been questioned over the last years [Bornot A, Bauer U, Brown A,
Firth M, Hellawell C, Engkvist O. Systematic Exploration of
Dual-Acting Modulators from a Combined Medicinal Chemistry and
Biology Perspective. J. Med. Chem, 56, 1197-1210 (2013)].
In a particular aspect, the present invention is directed to
compounds of general Formula (I):
##STR00002## wherein m is 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; X
is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; wherein
R.sub.x is selected from halogen, --OR.sub.8, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.x', is selected from hydrogen, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.8 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; W is nitrogen or carbon; R.sub.1 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.2 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heterocyclyl,
R.sub.3 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, --NR.sub.7R.sub.7' and
--CH.sub.2OR.sub.7; wherein R.sub.7 and R.sub.7' are independently
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; R.sub.4 and R.sub.4' are independently
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl, R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.6 and R.sub.6' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; and wherein
##STR00003## is selected from
##STR00004## wherein R.sub.n is selected from unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl;
These compounds according to the invention are optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In a particular embodiment the following proviso applies:
--[CR.sub.5R.sub.5'].sub.m--X--(CR.sub.6R.sub.6').sub.n--R.sub.2 is
not unsubstituted methyl.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound of general Formula (I')
##STR00005## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, m, n and p are as defined
in the description.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound of general Formula (I.sup.2')
##STR00006## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', X, m and p are as defined in the
description.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound of general Formula (I.sup.3')
##STR00007## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in
the description.
In a further embodiment, for compounds of general Formula (I)
described above in which
##STR00008## the compounds are thus compounds of general Formula
(I.sup.4')
##STR00009## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', R.sub.n, X, W, m, n and p are
as defined in the description.
In a further embodiment, for compounds of general Formula (I)
described above in which
##STR00010## the compounds are thus compounds of general Formula
(I.sup.5')
##STR00011## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', R.sub.n, X, W, m, n and p are
as defined in the description.
In a further embodiment, for compounds of general Formula (I)
described above in which
##STR00012## the compounds are thus compounds of general Formula
(I.sup.6')
##STR00013## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, W, m, n and p are as
defined in the description.
In a further embodiment, for compounds of general Formula (I)
described above in which
##STR00014## the compounds are thus compounds of general Formula
(I.sup.7')
##STR00015## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, W, m, n and p are as
defined in the description.
For clarity purposes, reference is also made to the following
statements below in the definitions of substitutions on alkyl etc.
or aryl etc. that "wherein when different radicals R.sub.1 to
(R.sub.13'''') R.sub.14'''' and R.sub.x, R.sub.x', R.sub.y and
R.sub.n are present simultaneously in Formula I they may be
identical or different". This statement is reflected in the below
general Formula (I.sup.2a') being derived from and falling into
general Formula (I.sup.2') as well as Formula (I).
##STR00016## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', X and p are as defined in the description. In
addition, m' (being 0 or 1), R.sub.5'' and R.sub.5''' are added. As
said above, this statement is thus reflected in that R.sub.5'' and
R.sub.5''' are or could be different from R.sub.5 and R.sub.5' or
not and--accordingly--m' being 0 or 1 is naturally resulting from m
(in general Formulas (I) or (I.sup.2') being 1 or 2).
The same would be applicable mutatis mutandis for general Formulas
like general Formula (I) or general Formula (I') as well as the
other general Formulas (I.sup.4') to (I.sup.7') above.
For clarity purposes, all groups and definitions described in the
description and referring to compounds of general Formula (I), also
apply to compounds of general Formula (I'), (I.sup.2'), (I.sup.3'),
(I.sup.4'), (I.sup.5'), (I.sub.6') or (I.sup.7') and also
(I.sup.2a') when those groups are present in the mentioned general
Markush formulae, since compounds of general Formula (I'),
(I.sup.2'), (I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.6') or
(I.sup.7') or (I.sup.2a') are included in the general Formula
(I).
For clarity purposes, the general Markush Formula (I)
##STR00017## is equivalent to
##STR00018## wherein only --C(R.sub.4R.sub.4')--,
--C(R.sub.5R.sub.5')-- and --C(R.sub.6R.sub.6')-- are included into
the brackets and p, m and n mean the number of times that
--C(R.sub.4R.sub.4')--, --C(R.sub.5R.sub.5')-- and
--C(R.sub.6R.sub.6')-- are repeated, respectively. The same would
apply to general Markush Formulae (I'), (I.sup.2'), (I.sup.2a'),
(I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.6') or (I.sup.7').
In addition, and for clarity purposes, it should further be
understood that naturally if p, m or n are 0, then X, R.sub.1 or
R.sub.2 are still present in general Markush Formulae (I), (I'),
(I.sup.2'), (I.sup.2a'), (I.sup.3'), (I.sup.4'), (I.sup.5'),
(I.sup.6') or (I.sup.7').
For the sake of clarity the expressions "compound according to
Formula (I) . . . , wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, m, n and p are
as defined in the description" or "compound according to Formula
(I) . . . , wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, W, m, n and p are as
defined in the description" would (just like the expression a
"compound of Formula (I) as defined in any one of claims 1 to 11"
found in the claims) refer to "a compound according to Formula (I)"
(or subformulas like Formula (I')), wherein the definitions of the
respective substituents R1 etc. (also from the cited claims) are
applied. In addition, this would also mean, though (especially in
regards to the claims) that also one or more of the disclaimers
defined in the description (or used in any of the cited claims like
e.g. claim 1) would be applicable to define the respective
compound. Thus, a disclaimer found in e.g. claim 1 would be also
used to define the compound "of Formula (I) as defined in any one
of claims 1 to 11".
In the context of this invention, alkyl is understood as meaning
saturated, linear or branched hydrocarbons, which may be
unsubstituted or substituted once or several times. It encompasses
e.g. --CH.sub.3 and --CH.sub.2--CH.sub.3. In these radicals,
C.sub.1-2-alkyl represents C1- or C2-alkyl, C.sub.1-3-alkyl
represents C1-, C2- or C3-alkyl, C.sub.1-4-alkyl represents C1-,
C2-, C3- or C4-alkyl, C.sub.1-5-alkyl represents C1-, C2-, C3-,
C4-, or C5-alkyl, C.sub.1-6-alkyl represents C1-, C2-, C3-, C4-,
C5- or C6-alkyl, C.sub.1-7-alkyl represents C1-, C2-, C3-, C4-,
C5-, C6- or C7-alkyl, C.sub.1-8-alkyl represents C1-, C2-, C3-,
C4-, C5-, C6-, C7- or C8-alkyl, C.sub.1-10-alkyl represents C1-,
C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and
C.sub.1-18-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-,
C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.
The alkyl radicals are preferably methyl, ethyl, propyl,
methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,
1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, hexyl, 1-methylpentyl, if substituted also
CHF.sub.2, CF.sub.3 or CH.sub.2OH etc. Preferably alkyl is
understood in the context of this invention as C.sub.1-8alkyl like
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl;
preferably is C.sub.1-6alkyl like methyl, ethyl, propyl, butyl,
pentyl, or hexyl; more preferably is C.sub.1-4alkyl like methyl,
ethyl, propyl or butyl.
Alkenyl is understood as meaning unsaturated, linear or branched
hydrocarbons, which may be unsubstituted or substituted once or
several times. It encompasses groups like e.g.
--CH.dbd.CH--CH.sub.3. The alkenyl radicals are preferably vinyl
(ethenyl), allyl (2-propenyl). Preferably in the context of this
invention alkenyl is C.sub.2-10-alkenyl or C.sub.2-8-alkenyl like
ethylene, propylene, butylene, pentylene, hexylene, heptylene or
octylene; or is C.sub.2-6-alkenyl like ethylene, propylene,
butylene, pentylene, or hexylene; or is C.sub.2-4-alkenyl, like
ethylene, propylene, or butylenes.
Alkynyl is understood as meaning unsaturated, linear or branched
hydrocarbons, which may be unsubstituted or substituted once or
several times. It encompasses groups like e.g.
--C.ident.C--CH.sub.3 (1-propinyl). Preferably alkynyl in the
context of this invention is C.sub.2-10-alkynyl or
C.sub.2-8-alkynyl like ethyne, propyne, butyene, pentyne, hexyne,
heptyne, or octyne; or is C.sub.2-6-alkynyl like ethyne, propyne,
butyene, pentyne, or hexyne; or is C.sub.2-4-alkynyl like ethyne,
propyne, butyene, pentyne, or hexyne.
In connection with alkyl (also in alkylaryl, alkylheterocyclyl or
alkylcycloalkyl), alkenyl, alkynyl and O-alkyl--unless defined
otherwise--the term substituted in the context of this invention is
understood as meaning replacement of at least one hydrogen radical
on a carbon atom by halogen (F, Cl, Br, I), --NR.sub.cR.sub.c''',
--SR.sub.c, --S(O)R.sub.c, --S(O).sub.2R.sub.c, --OR.sub.c,
--C(O)OR.sub.c, --CN, --C(O)NR.sub.cR.sub.c', haloalkyl, haloalkoxy
or --OC.sub.1-6alkyl being unsubstituted or substituted by one or
more of --OR.sub.c or halogen (F, Cl, I, Br), being R.sub.c
represented by R.sub.11, R.sub.12, R.sub.13, (being R.sub.c'
represented by R.sub.11', R.sub.12', R.sub.13'; being R.sub.c''
represented by R.sub.11'', R.sub.12'', R.sub.13''; being R.sub.c'''
represented by R.sub.11''', R.sub.12''', R.sub.13'''), being
R.sub.c'''' represented by R.sub.11'''', R.sub.12'''',
R.sub.13'''') wherein R.sub.1 to R.sub.14'''' and R.sub.x,
R.sub.x', R.sub.y and R.sub.n are as defined in the description,
and wherein when different radicals R.sub.1 to R.sub.14'''' and
R.sub.x, R.sub.x', R.sub.y and R.sub.n are present simultaneously
in Formula I they may be identical or different.
Most preferably in connection with alkyl (also in alkylaryl,
alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl,
substituted is understood in the context of this invention that any
alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl),
alkenyl, alkynyl or O-alkyl which is substituted is substituted
with one or more of halogen (F, Cl, Br, I), --OR.sub.c, --CN,
--SR.sub.c, --S(O)R.sub.c, and --S(O).sub.2R.sub.c, haloalkyl,
haloalkoxy or --OC.sub.1-6alkyl being unsubstituted or substituted
by one or more of --OR.sub.c or halogen (F, Cl, I, Br), being
R.sub.c represented by R.sub.11, R.sub.12, R.sub.10, (being
R.sub.c' represented by R.sub.11', R.sub.12', R.sub.13'; being
R.sub.c'' represented by R.sub.11'', R.sub.12'', R.sub.13''; being
R.sub.c''' represented by R.sub.11''', R.sub.12''', R.sub.13''',
being R.sub.c'''' represented by R.sub.11'''', R.sub.12'''',
R.sub.13''''), wherein R.sub.1 to R.sub.14'''' and R.sub.x,
R.sub.x', R.sub.y and R.sub.n are as defined in the description,
and wherein when different radicals R.sub.1 to R.sub.14'''' and
R.sub.x, R.sub.x', R.sub.y and R.sub.n are present simultaneously
in Formula I, they may be identical or different.
More than one replacement on the same molecule and also on the same
carbon atom is possible with the same or different substituents.
This includes for example 3 hydrogens being replaced on the same C
atom, as in the case of CF.sub.3, or at different places of the
same molecule, as in the case of e.g.
--CH(OH)--CH.dbd.CH--CHCl.sub.2.
In the context of this invention haloalkyl is understood as meaning
an alkyl being substituted once or several times by a halogen
(selected from F, Cl, Br, I). It encompasses e.g. --CH.sub.2Cl,
--CH.sub.2F, --CHCl.sub.2, --CHF.sub.2, --CCl.sub.3, --CF.sub.3 and
--CH.sub.2--CHCl.sub.2. Preferably haloalkyl is understood in the
context of this invention as halogen-substituted C.sub.1-4-alkyl
representing halogen substituted C1-, C2-, C3- or C4-alkyl. The
halogen-substituted alkyl radicals are thus preferably methyl,
ethyl, propyl, and butyl. Preferred examples include --CH.sub.2Cl,
--CH.sub.2F, --CHCl.sub.2, --CHF.sub.2, and --CF.sub.3.
In the context of this invention haloalkoxy is understood as
meaning an --O-alkyl being substituted once or several times by a
halogen (selected from F, Cl, Br, I). It encompasses e.g.
--OCH.sub.2Cl, --OCH.sub.2F, --OCHCl.sub.2, --OCHF.sub.2,
--OCCl.sub.3, --OCF.sub.3 and --OCH.sub.2--CHCl.sub.2. Preferably
haloalkyl is understood in the context of this invention as
halogen-substituted --OC.sub.1-4-alkyl representing halogen
substituted C1-, C2-, C3- or C4-alkoxy. The halogen-substituted
alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and
O-butyl. Preferred examples include --OCH.sub.2Cl, --OCH.sub.2F,
--OCHCl.sub.2, --OCHF.sub.2, and --OCF.sub.3.
In the context of this invention cycloalkyl is understood as
meaning saturated and unsaturated (but not aromatic) cyclic
hydrocarbons (without a heteroatom in the ring), which can be
unsubstituted or once or several times substituted. Furthermore,
C.sub.3-4-cycloalkyl represents C3- or C4-cycloalkyl,
C.sub.3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl,
C.sub.3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl,
C.sub.3-7-cycloalkyl represents C3-, C4-, C5-, C6- or
C7-cycloalkyl, C.sub.3-8-cycloalkyl represents C3-, C4-, C5-, C6-,
C7- or C8-cycloalkyl, C.sub.4-6-cycloalkyl represents C4- or
C5-cycloalkyl, C.sub.4-6-cycloalkyl represents C4-, C5- or
C6-cycloalkyl, C.sub.4-7-cycloalkyl represents C4-, C5-, C6- or
C7-cycloalkyl, C.sub.5-6-cycloalkyl represents C5- or C6-cycloalkyl
and C.sub.5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl.
Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl,
cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl,
cycloheptyl, cyclooctyl, and also adamantly. Preferably in the
context of this invention cycloalkyl is C.sub.3-8cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; or is C.sub.3-7cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl; or is C.sub.3-6cycloalkyl
like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially
cyclopentyl or cyclohexyl.
Aryl is understood as meaning 5 to 18 membered mono or polycyclic
ring systems with at least one aromatic ring but without
heteroatoms even in only one of the rings. Examples are phenyl,
naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl,
9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or
once or several times substituted. Most preferably aryl is
understood in the context of this invention as phenyl, naphtyl or
anthracenyl, preferably is phenyl.
A heterocyclyl radical or group (also called heterocyclyl
hereinafter) is understood as meaning 5 to 18 membered mono or
polycyclic heterocyclic ring systems, with at least one saturated
or unsaturated ring which contains one or more heteroatoms from the
group consisting of nitrogen, oxygen and/or sulfur in the ring. A
heterocyclic group can also be substituted once or several
times.
Examples include non-aromatic heterocyclyls such as
tetrahydropyrane, oxazepane, morpholine, piperidine, pyrrolidine as
well as heteroaryls such as furan, benzofuran, thiophene,
benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline,
isoquinoline, phthalazine, thiazole, benzothiazole, indole,
benzotriazole, carbazole and quinazoline.
Subgroups inside the heterocyclyls as understood herein include
heteroaryls and non-aromatic heterocyclyls. the heteroaryl (being
equivalent to heteroaromatic radicals or aromatic heterocyclyls) is
an aromatic 5 to 18 membered mono or polycyclic heterocyclic ring
system of one or more rings of which at least one aromatic ring
contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is an
aromatic heterocyclic ring system of one or two rings of which at
least one aromatic ring contains one or more heteroatoms from the
group consisting of nitrogen, oxygen and/or sulfur in the ring,
more preferably is selected from furan, benzofuran, thiophene,
benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline,
isoquinoline, phthalazine, benzothiazole, indole, benzotriazole,
carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole,
thiophene and benzimidazole; the non-aromatic heterocyclyl is a 5
to 18 membered mono or polycyclic heterocyclic ring system of one
or more rings of which at least one ring with this (or these)
ring(s) then not being aromatic--contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two rings
of which one or both rings--with this one or two rings then not
being aromatic--contain/s one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from oxazepam, pyrrolidine, piperidine,
piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine,
benzodioxane, oxetane, especially is benzodioxane, morpholine,
tetrahydropyran, piperidine, oxopyrrolidine, oxetane and
pyrrolidine.
Preferably in the context of this invention heterocyclyl is defined
as a 5 to 18 membered mono or polycyclic heterocyclic ring system
of one or more saturated or unsaturated rings of which at least one
ring contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to
18 membered mono or polycyclic heterocyclic ring system of one or
two saturated or unsaturated rings of which at least one ring
contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring.
Preferred examples of heterocyclyls include oxetane, oxazepan,
pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine,
pyrimidine, piperidine, piperazine, benzofuran, benzimidazole,
indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline, especially is pyridine, pyrazine, indazole,
benzodioxane, thiazole, benzothiazole, morpholine,
tetrahydropyrane, pyrazole, imidazole, piperidine, thiophene,
indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole,
oxopyrrolidine, pyrimidine, oxazepane, oxetane and pyrrolidine.
In the context of this invention oxopyrrolidine is understood as
meaning pyrrolidin-2-one.
In connection with aromatic heterocyclyls (heteroaryls),
non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring
system falls within two or more of the above cycle definitions
simultaneously, then the ring system is defined first as an
aromatic heterocyclyl (heteroaryl) if at least one aromatic ring
contains a heteroatom. If no aromatic ring contains a heteroatom,
then the ring system is defined as a non-aromatic heterocyclyl if
at least one non-aromatic ring contains a heteroatom. If no
non-aromatic ring contains a heteroatom, then the ring system is
defined as an aryl if it contains at least one aryl cycle. If no
aryl is present, then the ring system is defined as a cycloalkyl if
at least one non-aromatic cyclic hydrocarbon is present.
In the context of this invention alkylaryl is understood as meaning
an aryl group (see above) being connected to another atom through a
C.sub.1-6-alkyl (see above) which may be branched or linear and is
unsubstituted or substituted once or several times. Preferably
alkylaryl is understood as meaning an aryl group (see above) being
connected to another atom through 1 to 4 (--CH.sub.2--) groups.
Most preferably alkylaryl is benzyl (i.e. --CH.sub.2-phenyl).
In the context of this invention alkylheterocyclyl is understood as
meaning an heterocyclyl group being connected to another atom
through a C.sub.1-6-alkyl (see above) which may be branched or
linear and is unsubstituted or substituted once or several times.
Preferably alkylheterocyclyl is understood as meaning an
heterocyclyl group (see above) being connected to another atom
through 1 to 4 (--CH.sub.2--) groups. Most preferably
alkylheterocyclyl is --CH.sub.2-pyridine.
In the context of this invention alkylcycloalkyl is understood as
meaning an cycloalkyl group being connected to another atom through
a C.sub.1-6-alkyl (see above) which may be branched or linear and
is unsubstituted or substituted once or several times. Preferably
alkylcycloalkyl is understood as meaning an cycloalkyl group (see
above) being connected to another atom through 1 to 4
(--CH.sub.2--) groups. Most preferably alkylcycloalkyl is
--CH.sub.2-cyclopropyl.
Preferably, the aryl is a monocyclic aryl. More preferably the aryl
is a 5, 6 or 7 membered monocyclic aryl. Even more preferably the
aryl is a 5 or 6 membered monocyclic aryl.
Preferably, the heteroaryl is a monocyclic heteroaryl. More
preferably the heteroaryl is a 5, 6 or 7 membered monocyclic
heteroaryl. Even more preferably the heteroaryl is a 5 or 6
membered monocyclic heteroaryl.
Preferably, the non-aromatic heterocyclyl is a monocyclic
non-aromatic heterocyclyl. More preferably the non-aromatic
heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic
heterocyclyl. Even more preferably the non-aromatic heterocyclyl is
a 5 or 6 membered monocyclic non-aromatic heterocyclyl.
Preferably, the cycloalkyl is a monocyclic cycloalkyl. More
preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered
monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3,
4, 5 or 6 membered monocyclic cycloalkyl.
In connection with aryl (including alkyl-aryl), cycloalkyl
(including alkyl-cycloalkyl), or heterocyclyl (including
alkyl-heterocyclyl), substituted is understood--unless defined
otherwise--as meaning substitution of the ring-system of the aryl
or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocyclyl or
alkyl-heterocyclyl with one or more of halogen (F, Cl, Br, I),
--R.sub.c, --OR.sub.c, --CN, --NO.sub.2, --NR.sub.cR.sub.c''',
--C(O)OR.sub.c, NR.sub.cC(O)R.sub.c', --C(O)NR.sub.cR.sub.c',
--NR.sub.cS(O).sub.2R.sub.c', .dbd.O, --OCH.sub.2CH.sub.2OH,
--NR.sub.cC(O)NR.sub.c'R.sub.c'', --S(O).sub.2NR.sub.cR.sub.c',
--NR.sub.cS(O).sub.2NR.sub.c'R.sub.c'', haloalkyl, haloalkoxy,
--SR.sub.c, --S(O)R.sub.c, --S(O).sub.2R.sub.c or
C(CH.sub.3)OR.sub.c; NR.sub.cR.sub.c''', with R.sub.c and
R.sub.c''' independently being either H or a saturated or
unsaturated, linear or branched, substituted or unsubstituted
C.sub.1-6-alkyl; a saturated or unsaturated, linear or branched,
substituted or unsubstituted C.sub.1-6-alkyl; a saturated or
unsaturated, linear or branched, substituted or unsubstituted
--O--C.sub.1-6-alkyl (alkoxy); a saturated or unsaturated, linear
or branched, substituted or unsubstituted --S--C.sub.1-6-alkyl; a
saturated or unsaturated, linear or branched, substituted or
unsubstituted --C(O)--C.sub.1-6-alkyl-group; a saturated or
unsaturated, linear or branched, substituted or unsubstituted
--C(O)--O--C.sub.1-6-alkyl-group; a substituted or unsubstituted
aryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl or
alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or
alkyl-heterocyclyl, being R.sub.c one of R.sub.11, R.sub.12 or
R.sub.14, (being R.sub.c' one of R.sub.11', R.sub.12' or R.sub.14';
being R.sub.c'' one of R.sub.11'', R.sub.12'' or R.sub.14''; being
R.sub.c''' one of R.sub.11''', R.sub.12''' or R.sub.14'''; being
R.sub.c'''' one of R.sub.11'''', R.sub.12'''' or R.sub.14''''),
wherein R.sub.1 to R.sub.14'''' and R.sub.x, R.sub.x', R.sub.y are
as defined in the description, and wherein when different radicals
R.sub.1 to R.sub.14'''' and R.sub.x, R.sub.x', R.sub.y and R.sub.n
are present simultaneously in Formula I they may be identical or
different.
Most preferably in connection with aryl (including alkyl-aryl),
cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including
alkyl-heterocyclyl), substituted is understood in the context of
this invention that any aryl, cycloalkyl and heterocyclyl which is
substituted is substituted (also in an alyklaryl, alkylcycloalkyl
or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I),
--R.sub.c, --OR.sub.c, --CN, --NO.sub.2, --NR.sub.cR.sub.c''',
NR.sub.cC(O)R.sub.c', --NR.sub.cS(O).sub.2R.sub.c', .dbd.O,
haloalkyl, haloalkoxy, or C(CH.sub.3)OR.sub.c; --OC.sub.1-4alkyl
being unsubstituted or substituted with one or more of OR.sub.c or
halogen (F, Cl, I, Br), --CN, or --C.sub.1-4alkyl being
unsubstituted or substituted with one or more of OR.sub.c or
halogen (F, Cl, I, Br), being R.sub.c one of R.sub.11, R.sub.12 or
R.sub.14, (being R.sub.c' one of R.sub.11', R.sub.12' or R.sub.14';
being R.sub.c'' one of R.sub.11'', R.sub.12'' or R.sub.14''; being
R.sub.c''' one of R.sub.11''', R.sub.12''' or R.sub.14'''; being
R.sub.c'''' one of R.sub.11'''', R.sub.12'''' or R.sub.14''''),
wherein R.sub.1 to R.sub.14'''' and R.sub.x, R.sub.x' and R.sub.y
are as defined in the description, and wherein when different
radicals R.sub.1 to R.sub.14'''' and R.sub.x, R.sub.x', R.sub.y and
R.sub.n are present simultaneously in Formula I they may be
identical or different.
Additionally to the above-mentioned substitutions, in connection
with cycloalkyl (including alkyl-cycloalkyl), or heterocycly
(including alkylheterocyclyl) namely non-aromatic heterocyclyl
(including non-aromatic alkyl-heterocyclyl), substituted is also
understood--unless defined otherwise--as meaning substitution of
the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic
heterocyclyl or non aromatic alkyl-heterocyclyl with
##STR00019## or .dbd.O.
A ring system is a system consisting of at least one ring of
connected atoms but including also systems in which two or more
rings of connected atoms are joined with "joined" meaning that the
respective rings are sharing one (like a spiro structure), two or
more atoms being a member or members of both joined rings.
The term "leaving group" means a molecular fragment that departs
with a pair of electrons in heterolytic bond cleavage. Leaving
groups can be anions or neutral molecules. Common anionic leaving
groups are halides such as Cl--, Br--, and I--, and sulfonate
esters, such as tosylate (TsO--) or mesylate.
The term "salt" is to be understood as meaning any form of the
active compound used according to the invention in which it assumes
an ionic form or is charged and is coupled with a counter-ion (a
cation or anion) or is in solution. By this are also to be
understood complexes of the active compound with other molecules
and ions, in particular complexes via ionic interactions.
The term "physiologically acceptable salt" means in the context of
this invention any salt that is physiologically tolerated (most of
the time meaning not being toxic-especially not caused by the
counter-ion) if used appropriately for a treatment especially if
used on or applied to humans and/or mammals.
These physiologically acceptable salts can be formed with cations
or bases and in the context of this invention is understood as
meaning salts of at least one of the compounds used according to
the invention--usually a (deprotonated) acid--as an anion with at
least one, preferably inorganic, cation which is physiologically
tolerated--especially if used on humans and/or mammals. The salts
of the alkali metals and alkaline earth metals are particularly
preferred, and also those with NH.sub.4, but in particular (mono)-
or (di)sodium, (mono)- or (di)potassium, magnesium or calcium
salts.
Physiologically acceptable salts can also be formed with anions or
acids and in the context of this invention is understood as meaning
salts of at least one of the compounds used according to the
invention as the cation with at least one anion which are
physiologically tolerated--especially if used on humans and/or
mammals. By this is understood in particular, in the context of
this invention, the salt formed with a physiologically tolerated
acid, that is to say salts of the particular active compound with
inorganic or organic acids which are physiologically
tolerated--especially if used on humans and/or mammals. Examples of
physiologically tolerated salts of particular acids are salts of:
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid, malic
acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or
citric acid.
The compounds of the invention may be present in crystalline form
or in the form of free compounds like a free base or acid.
Any compound that is a solvate of a compound according to the
invention like a compound according to general formula I defined
above is understood to be also covered by the scope of the
invention. Methods of solvation are generally known within the art.
Suitable solvates are pharmaceutically acceptable solvates. The
term "solvate" according to this invention is to be understood as
meaning any form of the active compound according to the invention
in which this compound has attached to it via non-covalent binding
another molecule (most likely a polar solvent). Especially
preferred examples include hydrates and alcoholates, like
methanolates or ethanolates.
Any compound that is a prodrug of a compound according to the
invention like a compound according to general formula I defined
above is understood to be also covered by the scope of the
invention. The term "prodrug" is used in its broadest sense and
encompasses those derivatives that are converted in vivo to the
compounds of the invention. Such derivatives would readily occur to
those skilled in the art, and include, depending on the functional
groups present in the molecule and without limitation, the
following derivatives of the present compounds: esters, amino acid
esters, phosphate esters, metal salts sulfonate esters, carbamates,
and amides. Examples of well known methods of producing a prodrug
of a given acting compound are known to those skilled in the art
and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug
design and Discovery" Taylor & Francis (April 2002).
Unless otherwise stated, the compounds of the invention are also
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of a hydrogen by
a deuterium or tritium, or the replacement of a carbon by .sup.13C-
or .sup.14C-enriched carbon or of a nitrogen by .sup.15N-enriched
nitrogen are within the scope of this invention.
The compounds of formula (I) as well as their salts or solvates of
the compounds are preferably in pharmaceutically acceptable or
substantially pure form. By pharmaceutically acceptable form is
meant, inter alia, having a pharmaceutically acceptable level of
purity excluding normal pharmaceutical additives such as diluents
and carriers, and including no material considered toxic at normal
dosage levels. Purity levels for the drug substance are preferably
above 50%, more preferably above 70%, most preferably above 90%. In
a preferred embodiment it is above 95% of the compound of formula
(I), or of its salts. This applies also to its solvates or
prodrugs.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
wherein
m is 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
X is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--;
wherein R.sub.x is selected from halogen, --OR.sub.8, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.x' is selected from hydrogen, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.8 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; W is nitrogen or carbon; R.sub.1 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in
R.sub.1 if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.11, --OR.sub.11,
--NO.sub.2, --NR.sub.11R.sub.11''', NR.sub.11C(O)R.sub.11',
--NR.sub.11S(O).sub.2R.sub.11', --S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with
##STR00020## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.1, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.11, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.11, --S(O)R.sub.11, and --S(O).sub.2R.sub.11;
wherein R.sub.11, R.sub.11' and R.sub.11'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.12, --OR.sub.12,
--NO.sub.2, --NR.sub.12R.sub.12''', NR.sub.12C(O)R.sub.12',
--NR.sub.12S(O).sub.2R.sub.12', --S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00021## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.12, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.12, --S(O)R.sub.12, and --S(O).sub.2R.sub.12;
wherein R.sub.12, R.sub.12' and R.sub.12'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.12''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.3 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --NR.sub.7R.sub.7' and --CH.sub.2OR.sub.7; wherein
R.sub.7 and R.sub.7' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl, R.sub.5 and R.sub.5' are independently selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; R.sub.6 and R.sub.6' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; and wherein
##STR00022## is selected from
##STR00023## wherein R.sub.n is selected from unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; the alkyl, alkenyl or alkynyl, other than those
defined in R.sub.1 or R.sub.2, if substituted, is substituted with
one or more substituent/s selected from --OR.sub.13, halogen, --CN,
haloalkyl, haloalkoxy, --SR.sub.13, --S(O)R.sub.13, and
--S(O).sub.2R.sub.13; wherein R.sub.13, and R.sub.13' are
independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6
alkynyl; the aryl, heterocyclyl or cycloalkyl other than those
defined in R.sub.1 or R.sub.2, if substituted, is substituted with
one or more substituent/s selected from halogen, --R.sub.14,
--OR.sub.14, --NO.sub.2, --NR.sub.14R.sub.14''',
NR.sub.14C(O)R.sub.14', --NR.sub.14S(O).sub.2R.sub.14',
--S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1 or
R.sub.2, if substituted, may also be substituted with
##STR00024## or .dbd.O; wherein R.sub.14, R.sub.14' and R.sub.14''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and
unsubstituted heterocyclyl; and wherein R.sub.14''' is selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
These preferred compounds according to the invention are optionally
in form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
m is 1 or 2;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
n is 0, 1 or 2;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general f Formula (I) is a compound wherein
p is 0, 1 or 2;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general f Formula (I) is a compound wherein
W is nitrogen or carbon;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general f Formula (I) is a compound wherein
W is nitrogen;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general f Formula (I) is a compound wherein
W is carbon;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
X is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
X is a bond;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
X is --C(R.sub.xR.sub.x')--;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
X is C.dbd.O;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
X is --O--;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
R.sub.1 is selected from substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
R.sub.2 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl, optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In a further embodiment the compound according to the invention of
general Formula (I) is a compound wherein
R.sub.2 is substituted or unsubstituted aryl,
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
according to the invention of general Formula (I) is a compound
wherein
R.sub.3 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, --NR.sub.7R.sub.7' and
--CH.sub.2OR.sub.7; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
according to the invention of general Formula (I) is a compound
wherein
R.sub.3 is substituted or unsubstituted C.sub.1-6 alkyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.4 and R.sub.4' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl,
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.6 and R.sub.6' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.7 and R.sub.7' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.8 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.11,
R.sub.11' and R.sub.11'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11''' is
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.11,
R.sub.11' and R.sub.11'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.11'''
is selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.12,
R.sub.12' and R.sub.12'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12''' is
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.12,
R.sub.12' and R.sub.12'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.12'''
is selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.13, and R.sub.13' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and
unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.14,
R.sub.14' and R.sub.14'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl and unsubstituted heterocyclyl; and wherein R.sub.14'''
is selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.14,
R.sub.14' and R.sub.14'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl and unsubstituted heterocyclyl; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.14'''
is selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.x is
selected from halogen, --OR.sub.8, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x' is
selected from hydrogen, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.x is
selected from halogen, --OR.sub.8, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.x is
selected from halogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein R.sub.x' is
selected from hydrogen, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.n is selected from unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
##STR00025## is selected from
##STR00026## optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I) is a compound wherein
##STR00027## optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In another preferred embodiment of the compound according to the
invention of general Formula (I), is a compound wherein
m is 1 or 2; and/or
n is 0, 1 or 2; and/or
p is 0, 1 or 2; and/or
X is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; and/or
W is nitrogen or carbon; and/or
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; wherein the C.sub.1-6 alkyl is
preferably selected from methyl, ethyl, propyl, butyl, pentyl,
hexyl, isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl
is preferably selected from ethylene, propylene, butylene,
pentylene and hexylene; and/or the C.sub.2-6-alkynyl is preferably
selected from ethyne, propyne, butyne, pentyne and hexyne; and/or
the aryl is selected from phenyl, naphtyl, or anthracene;
preferably is napthyl and phenyl; more preferably is phenyl; and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline, more preferably the
heterocycle is pyridine: the cycloalkyl is C.sub.3-8 cycloalkyl
like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; and/or R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; wherein the C.sub.1-6 alkyl is preferably selected
from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or the aryl is selected from
phenyl, naphtyl and anthracene; preferably is napthyl or phenyl;
more preferably is phenyl; and/or the heterocyclyl is a
heterocyclic ring system of one or more saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring, more preferably is selected from
imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,
piperazine, benzofuran, benzimidazole, indazole, benzothiazole,
benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline: and/or the cycloalkyl is C.sub.3-8 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; and/or R.sub.3 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --NR.sub.7R.sub.7' and --CH.sub.2OR.sub.7; wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more
preferably the C.sub.1-6 alkyl is ethyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or the aryl is selected from phenyl, naphtyl and
anthracene; preferably is napthyl or phenyl; more preferably is
phenyl; and/or the heterocyclyl is a heterocyclic ring system of
one or more saturated or unsaturated rings of which at least one
ring contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is a
heterocyclic ring system of one or two saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring, more preferably is selected from imidazole, oxadiazole,
tetrazole, pyridine, pyrimidine, piperidine, piperazine,
benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,
thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline,
furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene,
pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline: and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or R.sub.4
and R.sub.4' are independently selected from hydrogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; wherein the C.sub.1-6 alkyl is preferably selected from
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.5 and R.sub.5' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.6 and R.sub.6' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is preferably
selected from methyl, ethyl, propyl, butyl, pentyl, hexyl,
isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.7
and R.sub.7' are independently selected from hydrogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heterocyclyl;
wherein the C.sub.1-6 alkyl is preferably selected from methyl,
ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.8 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is preferably
selected from methyl, ethyl, propyl, butyl, pentyl, hexyl,
isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.11,
R.sub.11' and R.sub.11'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11''' is
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; wherein the C.sub.1-6 alkyl is preferably selected from
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.12, R.sub.12' and
R.sub.12'' are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; and wherein R.sub.12''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.13, and R.sub.13' are independently selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.14, R.sub.14' and R.sub.14'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted
heterocyclyl; and wherein R.sub.14''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; wherein the C.sub.1-6
alkyl is preferably selected from methyl, ethyl, propyl, butyl,
pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or the heterocyclyl is a heterocyclic ring system of
one or more saturated or unsaturated rings of which at least one
ring contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is a
heterocyclic ring system of one or two saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring, more preferably is selected from imidazole, oxadiazole,
tetrazole, pyridine, pyrimidine, piperidine, piperazine,
benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,
thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline,
furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene,
pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or R.sub.x
is selected from halogen, --OR.sub.8, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.x' is selected from hydrogen, halogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is preferably
selected from methyl, ethyl, propyl, butyl, pentyl, hexyl,
isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.n is
selected from unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, preferably the
C.sub.1-6 alkyl is methyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.1
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphtyl, or anthracene;
preferably is napthyl and phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline, more preferably the
heterocycle is pyridine and/or the cycloalkyl is C.sub.3-8
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
more preferably from C.sub.3-6 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; optionally in form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.2
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphtyl and anthracene;
preferably is napthyl or phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline: and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.3
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more
preferably the C.sub.1-6 alkyl is ethyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphtyl and anthracene;
preferably is napthyl or phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline: and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.4
and R.sub.4' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.5
and R.sub.5' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.6
and R.sub.6' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.7
and R.sub.7' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphtyl and anthracene;
preferably is napthyl or phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline: and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.8
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.11, R.sub.11' and R.sub.11'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.11''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.12, R.sub.12' and R.sub.12'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.12''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.13, and R.sub.13' as defined in any of the embodiments of the
present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.14, R.sub.14' and R.sub.14'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
and/or
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in
R.sub.14''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.n
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.x
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein in R.sub.x'
as defined in any of the embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
n is 0, 1 or 2, preferably n is 0;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
m is 1 or 2; preferably m is 1;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
p is 0, 1 or 2; preferably p is 0;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
X is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; preferably,
X is a bond or --O--;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
##STR00028## W is nitrogen or carbon; preferably W is nitrogen, and
R.sub.n is unsubstituted C.sub.1-6 alkyl; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
##STR00029## W is nitrogen or carbon; preferably W is nitrogen;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein
##STR00030## W is nitrogen or carbon; preferably W is nitrogen, and
R.sub.n is unsubstituted C.sub.1-6 alkyl; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another preferred embodiment of the invention according to
general Formula (I), the compound is a compound of Formula (I')
##STR00031## wherein m is 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2; X
is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; wherein
R.sub.x is selected from halogen, --OR.sub.8, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.x' is selected from hydrogen, halogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.8 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; R.sub.1 is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; wherein said cycloalkyl,
aryl or heterocyclyl in R.sub.1 if substituted, is substituted with
one or more substituent/s selected from halogen, --R.sub.11,
--OR.sub.11, --NO.sub.2, --NR.sub.11R.sub.11''',
NR.sub.11C(O)R.sub.11', --NR.sub.11S(O).sub.2R.sub.11',
--S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with
##STR00032## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.1, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.11, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.11, --S(O)R.sub.11, and --S(O).sub.2R.sub.11;
wherein R.sub.11, R.sub.11' and R.sub.11'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.12, --OR.sub.12,
--NO.sub.2, --NR.sub.12R.sub.12''', NR.sub.12C(O)R.sub.12',
--NR.sub.12S(O).sub.2R.sub.12', --S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00033## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.12, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.12, --S(O)R.sub.12, and --S(O).sub.2R.sub.12;
wherein R.sub.12, R.sub.12' and R.sub.12'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.12''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.3 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --NR.sub.7R.sub.7' and --CH.sub.2OR.sub.7; wherein
R.sub.7 and R.sub.7' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl, R.sub.5 and R.sub.5' are independently selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; R.sub.6 and R.sub.6' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; the alkyl, alkenyl
or alkynyl, other than those defined in R.sub.1 or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.13, halogen, --CN, haloalkyl, haloalkoxy,
--SR.sub.13, --S(O)R.sub.13, and --S(O).sub.2R.sub.13; wherein
R.sub.13, and R.sub.13' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and
unsubstituted C.sub.2-6 alkynyl; the aryl, heterocyclyl or
cycloalkyl other than those defined in R.sub.1 or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from halogen, --R.sub.14, --OR.sub.14, --NO.sub.2,
--NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1 or
R.sub.2, if substituted, may also be substituted with
##STR00034## or .dbd.O; wherein R.sub.14, R.sub.14' and R.sub.14''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and
unsubstituted heterocyclyl; and wherein R.sub.14''' is selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein X is a
bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; preferably X is a
bond, C.dbd.O or --O--; more preferably X is a bond; and/or m is 1
or 2; preferably m is 1; and/or n is 0, 1 or 2; preferably n is 0;
and/or p is 0, 1 or 2; preferably p is 0; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound, wherein X is a
bond, --C(R.sub.xR.sub.x')--, C.dbd.O or --O--; preferably X is a
bond, C.dbd.O or --O--; more preferably X is a bond or --O--;
and/or m is 1 or 2; preferably m is 1 or 2; and/or n is 0, 1 or 2;
preferably n is 0; and/or p is 0, 1 or 2; preferably p is 0;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound of Formula
(I.sup.2'),
##STR00035## wherein X is a bond, --C(R.sub.xR.sub.x')--, C.dbd.O
or --O--; preferably X is a bond, C.dbd.O or --O--; more preferably
X is a bond; m is 1 or 2; preferably m is 1; and p is 0, 1 or 2;
preferably p is 0; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound of Formula
(I.sup.2a'),
##STR00036## wherein m' is 0 or 1; p is 0, 1 or 2; X is a bond,
--C(R.sub.xR.sub.x')--, C.dbd.O or --O--; wherein R.sub.x is
selected from halogen, --OR.sub.8, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x' is
selected from hydrogen, halogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; W is nitrogen or carbon; R.sub.1
is selected from substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl, substituted or
unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or
heterocyclyl in R.sub.1 if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.11, --OR.sub.11,
--NO.sub.2, --NR.sub.11R.sub.11''', NR.sub.11C(O)R.sub.11',
--NR.sub.11S(O).sub.2R.sub.11', --S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with
##STR00037## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.1, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.11, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.11, --S(O)R.sub.11, and --S(O).sub.2R.sub.11;
wherein R.sub.11, R.sub.11' and R.sub.11'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.12, --OR.sub.12,
--NO.sub.2, --NR.sub.12R.sub.12''', NR.sub.12C(O)R.sub.12',
--NR.sub.12S(O).sub.2R.sub.12', --S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00038## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.12, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.12, --S(O)R.sub.12, and --S(O).sub.2R.sub.12;
wherein R.sub.12, R.sub.12' and R.sub.12'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.12''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.3 is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --NR.sub.7R.sub.7' and --CH.sub.2OR.sub.7; wherein
R.sub.7 and R.sub.7' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl, R.sub.5 and R.sub.5' are independently selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; R.sub.5'' and R.sub.5''' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; the alkyl, alkenyl
or alkynyl, other than those defined in R.sub.1 or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.13, halogen, --CN, haloalkyl, haloalkoxy,
--SR.sub.13, --S(O)R.sub.13, and --S(O).sub.2R.sub.13; wherein
R.sub.13, and R.sub.13' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and
unsubstituted C.sub.2-6 alkynyl; the aryl, heterocyclyl or
cycloalkyl other than those defined in R.sub.1 or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from halogen, --R.sub.14, --OR.sub.14, --NO.sub.2,
--NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1 or
R.sub.2, if substituted, may also be substituted with
##STR00039## or .dbd.O; wherein R.sub.14, R.sub.14' and R.sub.14''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and
unsubstituted heterocyclyl; and wherein R.sub.14''' is selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I) the compound is a compound of Formula
(I.sup.3'),
##STR00040## optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I.sup.3') the compound is a compound, wherein
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; preferably R.sub.1 is selected from
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; more preferably R.sub.1 is substituted or
unsubstituted phenyl or substituted or unsubstituted pyridine;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I.sup.3') the compound is a compound, wherein
R.sub.2 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; preferably R.sub.2 is
substituted or unsubstituted aryl; more preferably R.sub.2 is
substituted or unsubstituted phenyl. optionally in form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In a further preferred embodiment of the invention according to
general Formula (I.sup.3') the compound is a compound, wherein
R.sub.3 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, --NR.sub.7R.sub.7' and
--CH.sub.2OR.sub.7; preferably R.sub.3 is substituted or
unsubstituted ethyl. optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment
R.sub.1 is a substituted or unsubstituted group selected from
phenyl and pyridine.
In a preferred embodiment
R.sub.2 is substituted or unsubstituted phenyl, preferably
unsubstituted phenyl.
In a preferred embodiment
R.sub.2 is substituted or unsubstituted alkyl, preferably
unsubstituted alkyl or alkyl substituted with --O-methyl or
substituted with --O-ethyl.
In a preferred embodiment
R.sub.2 is substituted or unsubstituted alkyl, preferably
unsubstituted alkyl, preferably substituted or unsubstituted
methyl, substituted or unsubstituted ethyl or substituted or
unsubstituted isopropyl, more preferably unsubstituted methyl,
unsubstituted ethyl or unsubstituted isopropyl.
In a preferred embodiment
R.sub.3 is substituted or unsubstituted ethyl.
In a preferred embodiment
R.sub.3 is unsubstituted ethyl.
In a preferred embodiment
R.sub.5 and R.sub.5' are both hydrogen.
In a preferred embodiment
X is a bond.
In a preferred embodiment
X is --O--.
In another preferred embodiment
n is 0;
In another preferred embodiment
n is 1.
In another preferred embodiment
m is 1.
In another preferred embodiment
m is 2.
In another preferred embodiment
p is 0.
In an particular embodiment
the halogen is fluorine or chlorine, preferably fluorine.
In a preferred further embodiment, the compounds of the general
Formula (I) are selected from
TABLE-US-00001 EX Chemical name 1
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(3-
fluoropyridin-2-yl)propionamide 2
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-
phenylpropionamide 3
(S)-N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-
phenylpropionamide 4
(R)-N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-
phenylpropionamide
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred further embodiment, the compounds of the general
Formula (I) are selected from
TABLE-US-00002 5
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-
(trifluoromethyl)pyridin-2-yl)propionamide 6 Enantiomer of 5 7
Enantiomer of 5 8
N-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-N-
(6-(trifluoromethyl)pyridin-2-yl)propionamide 9
N-(2-(3-(benzyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-
(trifluoromethyl)pyridin-2-yl)propionamide 10
N-(2-(3-(isobutyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-
(trifluoromethyl)pyridin-2-yl)propionamide 11
N-(2-(3-((2-methoxyethyl)(methyl)amino)azetidin-1-yl)ethyl)-N-
(6-(trifluoromethyl)pyridin-2-yl)propionamide 12
N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-
(trifluoromethyl)pyridin-2-yl)propionamide. 13 Enantiomer of 12 14
Enantiomer of 12 15
N-(2-(3-((2-ethoxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)-N-
(6-(trifluoromethyl)pyridin-2-yl)propionamide 16 Enantiomer of 15
17 Enantiomer of 15 18
N-(2-(5-isobutylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-N-
(6-(trifluoromethyl)pyridin-2-yl)propionamide 19
N-(2-(5-(2-ethoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-
yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I),
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or
heterocyclyl in R.sub.1 if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.11, --OR.sub.11,
--NO.sub.2, --NR.sub.11R.sub.11''', NR.sub.11C(O)R.sub.11',
--NR.sub.11S(O).sub.2R.sub.11', --S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with
##STR00041## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.1, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.11, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.11, --S(O)R.sub.11, and --S(O).sub.2R.sub.11;
wherein R.sub.11, R.sub.11' and R.sub.11'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another embodiment of the invention the compound of general
Formula (I),
R.sub.2 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl, wherein said cycloalkyl,
aryl or heterocyclyl in R.sub.2, if substituted, is substituted
with one or more substituent/s selected from halogen, --R.sub.12,
--OR.sub.12, --NO.sub.2, --NR.sub.12R.sub.12''',
NR.sub.12C(O)R.sub.12', --NR.sub.12S(O).sub.2R.sub.12',
--S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00042## or .dbd.O; wherein the alkyl, alkenyl or alkynyl in
R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.12, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.12, --S(O)R.sub.12, and --S(O).sub.2R.sub.12;
wherein R.sub.12, R.sub.12' and R.sub.12'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.12''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another embodiment of the invention the compound of general
Formula (I),
the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1
or R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.13, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.13, --S(O)R.sub.13, and
--S(O).sub.2R.sub.13;
wherein R.sub.13, and R.sub.13' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, and unsubstituted C.sub.2-6 alkynyl; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
In another embodiment of the invention the compound of general
Formula (I),
the aryl, heterocyclyl or cycloalkyl other than those defined in
R.sub.1 or R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.14, --OR.sub.14,
--NO.sub.2, --NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1 or
R.sub.2, if substituted, may also be substituted with
##STR00043## or .dbd.O; wherein R.sub.14, R.sub.14' and R.sub.14''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and
unsubstituted heterocyclyl; and wherein R.sub.14''' is selected
from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted
C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1 of any
of the embodiments of the present invention, the cycloalkyl, aryl
or heterocyclyl in R.sub.1 if substituted, is substituted with one
or more substituent/s selected from halogen, --R.sub.11,
--OR.sub.11, --NO.sub.2, --NR.sub.11R.sub.11''',
NR.sub.11C(O)R.sub.11', --NR.sub.11S(O).sub.2R.sub.11',
--S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --NR.sub.11S(O).sub.2NR.sub.11'R.sub.11''
and --C(CH.sub.3).sub.2OR.sub.11; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1 of any
of the embodiments of the present invention, the cycloalkyl or
non-aromatic heterocyclyl in R.sub.1, if substituted, may also be
substituted with
##STR00044## or .dbd.O; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1 of any
of the embodiments of the present invention,
the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is
substituted with one or more substituent/s selected from
--OR.sub.11, halogen, --CN, haloalkyl, haloalkoxy, --SR.sub.11,
--S(O)R.sub.11, and --S(O).sub.2R.sub.11;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention, the cycloalkyl, aryl
or heterocyclyl in R.sub.2, if substituted, is substituted with one
or more substituent/s selected from halogen, --R.sub.12,
--OR.sub.12, --NO.sub.2, --NR.sub.12R.sub.12''',
NR.sub.12C(O)R.sub.12', --NR.sub.12S(O).sub.2R.sub.12',
--S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --NR.sub.12S(O).sub.2NR.sub.12'R.sub.12''
and C(CH.sub.3).sub.2OR.sub.12; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention,
the cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if
substituted, may also be substituted with
##STR00045## or .dbd.O; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention,
the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is
substituted with one or more substituent/s selected from
--OR.sub.12, halogen, --CN, haloalkyl, haloalkoxy, --SR.sub.12,
--S(O)R.sub.12, and --S(O).sub.2R.sub.12;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to alkyls other
than those defined in R.sub.1 or R.sub.2 of any of the embodiments
of the present invention,
the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1
or R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.13, halogen, --CN, haloalkyl,
haloalkoxy, --SR.sub.13, --S(O)R.sub.13, and
--S(O).sub.2R.sub.13;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to the cycloalkyl,
aryl or heterocyclyl other than those defined in R.sub.1 or R.sub.2
of any of the embodiments of the present invention,
the aryl, heterocyclyl or cycloalkyl other than those defined in
R.sub.1 or R.sub.2, if substituted, is substituted with one or more
substituent/s selected from halogen, --R.sub.14, --OR.sub.14,
--NO.sub.2, --NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to to the
cycloalkyl, aryl or heterocyclyl other than those defined in
R.sub.1 or R.sub.2 of any of the embodiments of the present
invention,
the cycloalkyl or non-aromatic heterocyclyl, other than those
defined in R.sub.1 or R.sub.2, if substituted, may also be
substituted with
##STR00046## or .dbd.O; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
In an embodiment of the compound according to the invention of
general Formula (I),
the halogen is fluorine, chlorine, iodine or bromine, preferably
fluorine;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In a most preferred embodiment of the compound according to the
invention of general Formula (I)
the halogen is fluorine or chlorine, preferably fluorine:
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In an embodiment of the compound according to the invention of
general Formula (I),
the haloalkyl is --CF.sub.3;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
In another embodiment of the compound according to the invention of
general Formula (I),
the haloalkoxy is --OCF.sub.3;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
As this invention is aimed at providing a compound or a chemically
related series of compounds which act as dual ligands of the
.sigma..sub.1 receptor and the .mu.-opioid receptor it is a very
preferred embodiment in which the compounds are selected which act
as dual ligands of the .sigma..sub.1 receptor and the .mu.-opioid
receptor and especially compounds which have a binding expressed as
K.sub.1 which is preferably <1000 nM for both receptors, more
preferably <500 nM, even more preferably <100 nM.
In the following the phrase "compound of the invention" is used.
This is to be understood as any compound according to the invention
as described above according to general Formula (I), (I'),
(I.sup.2'), (I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.6') or
(I.sup.7') or (I.sup.2a').
The compounds of the invention represented by the above described
Formula (I) may include enantiomers depending on the presence of
chiral centres or isomers depending on the presence of multiple
bonds (e.g. Z, E). The single isomers, enantiomers or
diastereoisomers and mixtures thereof fall within the scope of the
present invention.
In general the processes are described below in the experimental
part. The starting materials are commercially available or can be
prepared by conventional methods.
A preferred aspect of the invention is also a process for the
production of a compound according to Formula (I), following scheme
1.
A preferred embodiment of the invention is a process for the
production of a compound according to Formula (I), wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.4', R.sub.5, R.sub.5', R.sub.6,
R.sub.6', X, W, m, n and p are as defined in the description,
following scheme 1.
In all processes and uses described underneath and in scheme 1, the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.4', R.sub.5,
R.sub.5', R.sub.6, R.sub.6', X, W, m, n and p are as defined in the
description, L is a leaving group such as halogen, mesylate,
tosylate or triflate, Z is chloro, bromo, hydroxy, methoxy or
ethoxy,
Y is
##STR00047## and PG is a protecting group, such as benzyl and
tert-butoxycarbonyl.
In a particular embodiment there is a process for the production of
a compound of Formula (I),
##STR00048## said process comprises reacting a compound of Formula
VII
##STR00049## with a compound of formula VIIIa through an alkylaton
reaction or VIIIb through a reductive amination reaction following
STEP 4 of scheme 1
##STR00050##
In a particular embodiment there is a process for the production of
a compound of Formula (I),
##STR00051## said process comprises an acylation of a compound of
Formula IVb
##STR00052## with a compound of formula Va or Vb following STEP 2
of scheme 1
##STR00053##
In a particular embodiment there is a process for the production of
a compound of Formula VII,
##STR00054## said process comprises a deprotection reaction of a
compound of Formula VI following STEP 3 of scheme 1
##STR00055##
In a particular embodiment there is a process for the production of
a compound of Formula VI,
##STR00056## said process comprises an acylation of a compound of
Formula IVa
##STR00057## with a compound of formula Va or Vb following STEP 2
of scheme 1
##STR00058##
In a particular embodiment there is a process for the production of
a compound of Formula Va or Vb,
##STR00059## said process comprises reacting a compound of Formula
IIa or IIb, respectively
##STR00060## with a compound of formula III following STEP 1 of
scheme 1
##STR00061##
In another particular embodiment a compound of Formula (IIa) or
(IIb),
##STR00062## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (III),
##STR00063## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (IVa) or
(IVb),
##STR00064## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (Va) or
(Vb),
##STR00065## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (VI),
##STR00066## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (VII),
##STR00067## is used for the preparation of a compound of Formula
(I).
In another particular embodiment a compound of Formula (VIIIa) or
(VIIIb),
##STR00068## is used for the preparation of a compound of Formula
(I).
The obtained reaction products may, if desired, be purified by
conventional methods, such as crystallisation and chromatography.
Where the above described processes for the preparation of
compounds of the invention give rise to mixtures of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. If there are chiral centers the
compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or
by resolution.
One preferred pharmaceutically acceptable form of a compound of the
invention is the crystalline form, including such form in
pharmaceutical composition. In the case of salts and also solvates
of the compounds of the invention the additional ionic and solvent
moieties must also be non-toxic. The compounds of the invention may
present different polymorphic forms, it is intended that the
invention encompasses all such forms.
Another aspect of the invention refers to a pharmaceutical
composition which comprises a compound according to the invention
as described above according to general formula I or a
pharmaceutically acceptable salt or steroisomer thereof, and a
pharmaceutically acceptable carrier, adjuvant or vehicle. The
present invention thus provides pharmaceutical compositions
comprising a compound of this invention, or a pharmaceutically
acceptable salt or stereoisomers thereof together with a
pharmaceutically acceptable carrier, adjuvant, or vehicle, for
administration to a patient.
Examples of pharmaceutical compositions include any solid (tablets,
pills, capsules, granules etc.) or liquid (solutions, suspensions
or emulsions) composition for oral, topical or parenteral
administration.
In a preferred embodiment the pharmaceutical compositions are in
oral form, either solid or liquid. Suitable dose forms for oral
administration may be tablets, capsules, syrops or solutions and
may contain conventional excipients known in the art such as
binding agents, for example syrup, acacia, gelatin, sorbitol,
tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,
sugar, maize starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate;
disintegrants, for example starch, polyvinylpyrrolidone, sodium
starch glycollate or microcrystalline cellulose; or
pharmaceutically acceptable wetting agents such as sodium lauryl
sulfate.
The solid oral compositions may be prepared by conventional methods
of blending, filling or tabletting. Repeated blending operations
may be used to distribute the active agent throughout those
compositions employing large quantities of fillers. Such operations
are conventional in the art. The tablets may for example be
prepared by wet or dry granulation and optionally coated according
to methods well known in normal pharmaceutical practice, in
particular with an enteric coating.
The pharmaceutical compositions may also be adapted for parenteral
administration, such as sterile solutions, suspensions or
lyophilized products in the appropriate unit dosage form. Adequate
excipients can be used, such as bulking agents, buffering agents or
surfactants.
The mentioned formulations will be prepared using standard methods
such as those described or referred to in the Spanish and US
Pharmacopoeias and similar reference texts.
Administration of the compounds or compositions of the present
invention may be by any suitable method, such as intravenous
infusion, oral preparations, and intraperitoneal and intravenous
administration. Oral administration is preferred because of the
convenience for the patient and the chronic character of the
diseases to be treated.
Generally an effective administered amount of a compound of the
invention will depend on the relative efficacy of the compound
chosen, the severity of the disorder being treated and the weight
of the sufferer. However, active compounds will typically be
administered once or more times a day for example 1, 2, 3 or 4
times daily, with typical total daily doses in the range of from
0.1 to 1000 mg/kg/day.
The compounds and compositions of this invention may be used with
other drugs to provide a combination therapy. The other drugs may
form part of the same composition, or be provided as a separate
composition for administration at the same time or at different
time.
Another aspect of the invention refers to the use of a compound of
the invention or a pharmaceutically acceptable salt or isomer
thereof in the manufacture of a medicament.
Another aspect of the invention refers to a compound of the
invention according as described above according to general formula
I, or a pharmaceutically acceptable salt or isomer thereof, for use
as a medicament for the treatment of pain. Preferably the pain is
medium to severe pain, visceral pain, chronic pain, cancer pain,
migraine, inflammatory pain, acute pain or neuropathic pain,
allodynia or hyperalgesia. This may include mechanical allodynia or
thermal hyperalgesia.
Another aspect of the invention refers to the use of a compound of
the invention in the manufacture of a medicament for the treatment
or prophylaxis of pain.
In a preferred embodiment the pain is selected from medium to
severe pain, visceral pain, chronic pain, cancer pain, migraine,
inflammatory pain, acute pain or neuropathic pain, allodynia or
hyperalgesia, also preferably including mechanical allodynia or
thermal hyperalgesia.
Another aspect of this invention relates to a method of treating or
preventing pain which method comprises administering to a patient
in need of such a treatment a therapeutically effective amount of a
compound as above defined or a pharmaceutical composition thereof.
Among the pain syndromes that can be treated are medium to severe
pain, visceral pain, chronic pain, cancer pain, migraine,
inflammatory pain, acute pain or neuropathic pain, allodynia or
hyperalgesia, whereas this could also include mechanical allodynia
or thermal hyperalgesia.
The present invention is illustrated below with the aid of
examples. These illustrations are given solely by way of example
and do not limit the general spirit of the present invention.
EXAMPLES
General Experimental Part (Methods and Equipment of the Synthesis
and Analysis
A process is described in Scheme 1 for the preparation of compounds
of general formula I, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', W and X have the
meanings defined above.
##STR00069##
Where, L is a leaving group such as halogen, mesylate, tosylate or
triflate and Z is chloro, bromo, hydroxy, methoxy or ethoxy, Y is
the group indicated in a square in Scheme 1 and PG is a protecting
group, such as benzyl or tert-butoxycarbonyl.
This process is carried out as described below:
Step 1: The compounds of formula IVa or IVb are prepared by
reacting a compound of formula IIa or IIb, respectively, with a
compound of formula III. Depending on the meaning of p and R.sub.1,
different reaction conditions will apply:
a) When p is 0 and R.sub.1 is aryl or heterocyclyl, compound III is
an arylating agent and L represents halogen (preferably bromo or
iodo) or triflate. This arylation reaction is carried out under
catalytic conditions using a palladium or copper catalyst, in the
presence of a suitable ligand and a suitable base, in a suitable
solvent, and at a suitable temperature, preferably heating at the
reflux temperature or in a microwave reactor. When using copper
catalysts such as copper iodide, L-proline is the preferred ligand,
potassium phosphate is used preferably as the base and
dimethylsulfoxide is the solvent of choice. When using palladium
catalysts, such as tris(dibenzylideneacetone)dipalladium or
palladium diacetate, 4,
5-bis(diphenylphosphino)-9,9-dimethylxanthene (XAMPHOS) or
2,2'-is(diphenylphosphino)-1,1'-binaphthyl (BINAP) are the
preferred ligands, cessium carbonate or sodium tert-butoxide are
used preferably as the base and 1,4-dioxane or toluene are the
solvents of choice. b) When p is 1 or 2, compound III is an
alkylating agent and L represents a leaving group such as halogen,
mesylate, tosylate or triflate. The alkylation reaction is carried
out in a suitable solvent, such as acetonitrile, dichloromethane,
1,4-dioxane or dimethylformamide, preferably in acetonitrile, in
the presence of an inorganic base such as K.sub.2CO.sub.3 or
Cs.sub.2CO.sub.3, or an organic base such as triethylamine or
diisopropylethylamine, preferably K.sub.2CO.sub.3, at a suitable
temperature comprised between room temperature and the reflux
temperature, preferably heating, or alternatively, the reactions
can be carried out in a microwave reactor. Additionally, an
activating agent, such as NaI, can be used. Step 2: Compounds of
general formula VI or I are prepared by acylation of the NH group
of compounds IVa or IVb. The acylating agent can be an acyl halide
of formula Va or an anhydride of formula Vb, and the reaction is
carried out in the presence of a suitable solvent, such as
acetonitrile, dichloromethane, 1,4-dioxane, 1,2-dicloroethane,
toluene or dimethylformamide, in the presence of an organic base
such as triethylamine, pyridine or diisopropylethylamine, at a
suitable temperature comprised between room temperature and the
reflux temperature, or alternatively, the reactions can be carried
out in a microwave reactor.
For compounds of general formula VI, wherein P is a protecting
group, two additional steps are necessary to obtain compounds of
formula I:
Step 3: A compound of formula VII is prepared by deprotection
reaction of a compound of formula VI. Deprotection is effected in
different conditions depending of the protecting group. If the
protecting group is benzyl the deprotection is carried out under
hydrogenation conditions, at a pressure comprised between 1 and 10
bars, in the presence of Pd, in a suitable solvent such as methanol
or ethanol, at a suitable temperature comprised between room
temperature and the reflux temperature, preferably at the reflux
temperature. If the protecting group is tert-butoxycarbonyl, the
deprotection is carried out in the presence of an inorganic acid
such as HCl or trifluoroacetic acid, preferably trifluoroacetic
acid, in a suitable solvent such as dichloromethane, at a suitable
temperature comprised between room temperature and the reflux
temperature, preferably at room temperature. Step 4: From
deprotected compounds of formula VII, compounds of general formula
I can be prepared by reaction with suitable reagents, such as those
of formula VIIIa-b, using different conditions depending on the
reagent nature. Thus:
The alkylation reaction with a compound of formula VIIIa is carried
out in a suitable solvent, such as acetonitrile, dichloromethane,
1,4-dioxane or dimethylformamide, preferably in acetonitrile, in
the presence of an inorganic base such as K.sub.2CO.sub.3 or
Cs.sub.2CO.sub.3, or an organic base such as triethylamine or
diisopropylethylamine, preferably diisopropylethylamine, at a
suitable temperature comprised between room temperature and the
reflux temperature, preferably heating, or alternatively, the
reactions can be carried out in a microwave reactor. Additionally,
an activating agent, such as NaI, can be used.
The reductive amination with a compound of formula VIIIb, is
carried out in the presence of a reductive reagent, preferably
sodium triacetoxyborohydride, in a suitable solvent, preferably
methanol, at a suitable temperature comprised between room
temperature and the reflux temperature, preferably in a microwave
reactor.
The process described by Steps 1 to 4 represents the general route
for the preparation of compounds of formula I. Additionally, the
functional groups present in any of the positions can be
interconverted using reactions known to those skilled in the
art.
Compounds of formula II, III, V and VIII where R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', W
and X have the meanings as defined above, are commercially
available or can be prepared by conventional methods described in
the bibliography. The preparation of compounds II wherein W is
nitrogen, involves the alkylation of a conveniently substituted
diamine compound with adequate protected or substituted halide
alkyl amines in the conditions previously described in step 4.
EXAMPLES
Intermediates and Examples
The following abbreviations are used in the examples:
AcOEt: Ethyl acetate
BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
Conc: Concentrated
CH: Cyclohexane
DCM: Dichloromethane
DIPEA: N,N-Diisopropylethylamine
EtOH: Ethanol
Ex: Example
h: Hour/s
HPLC: High-performance liquid chromatography
INT: Intermediate
MeOH: Methanol
MS: Mass spectrometry
Min: Minutes
Quant: Quantitative
Ret: Retention
rt: Room temperature
Sat: Saturated
TEA: Et.sub.3N, Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
Wt: Weight
The following method was used to obtain the HPLC-MS data:
A: Column Acquity UPLC BEH C18 2.1.times.50 mm, 1.7 .mu.m; flow
rate 0.61 mL/min; A: NH.sub.4HCO.sub.3 10 mM; B: ACN; Gradient: 0.3
min in 98% A, 98% A to 5% A in 2.7 min, 2 min in 0% A, 0% A to 98%
A in 0.2 min, 0.55 min in 98% A
B: Column: Aqcuity BEH C18 2.1.times.50 mm 1.7 .mu.m; flow rate 800
.mu.l/min; A: NH4HCO3 10 mM; B: ACN; Gradient: 0.3 min in 90% A,
90% A to 5% A in 2.7 min, 0.7 min in 5% A, 5% A to 90% A in 0.1
min, 1.2 min in 90% A
Intermediate 1. tert-Butyl
3-(methylsulfonyloxy)pyrrolidine-1-carboxylate
##STR00070##
Et.sub.3N (5.58 mL, 40 mmol) was added to a solution of tert-butyl
3-hydroxypyrrolidine-1-carboxylate (3 g, 16.02 mmol) in dry DCM (35
mL). The solution was cooled to 0.degree. C., stirred for 10 min
and then, methanesulfonyl chloride (2.1 mL, 27.24 mmol) was added
and the reaction mixture was stirred at 0.degree. C. After 1 h the
reaction mixture was allowed to warm to rt and stirred for 0.5 h.
The mixture was poured into ice-water and diluted with DCM. The
organic layer was washed with water, dried over Na.sub.2SO.sub.4,
filtered and evaporated to dryness to afford the title compound as
yellow oil (4.25 g, yield 99%) that was used in the next step
without further purification.
.sup.1H NMR (400 MHz, CDC13) .delta. ppm 1.49 (s, 9H) 2.08-2.21 (m,
1H) 2.29 (br. s., 1H) 3.07 (s, 3H) 3.36-3.64 (m, 3H) 3.65-3.75 (m,
1H) 5.28 (tt, J=4.23, 2.08 Hz, 1H))
Intermediate 2. tert-Butyl
3-(benzyl(methyl)amino)pyrrolidine-1-carboxylate
##STR00071##
A mixture of tert-butyl
3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (INT 1, 4.25 g,
16.02 mmol)) and N-Methyl-1-phenylmethanamine (6.20 mL, 48.07 mmol)
was stirred and heated at 100.degree. C. for 3 h, under nitrogen.
The residue was portioned between DCM/water. The aqueous phase was
further extracted with dichloromethane. The combined extracts were
washed with brine and dried (Na.sub.2SO.sub.4) filtered and
evaporated. The crude product thus obtained was purified by flash
chromatography on silica gel, gradient CH:AcOEt from (100:0) to
(70:30) to give the title compound as yellow oil (2.93 g, 63%
yield).
HPLC-MS (Method A): Ret, 2.20 min; ESI+-MS m/z, 291 (M+1).
Intermediate 3. N-Benzyl-N-methylpyrrolidin-3-amine
##STR00072##
Over a suspension of tert-butyl
3-(benzyl(methyl)amino)pyrrolidine-1-carboxylate (INT 2, 2.5 g,
8.71 mmol) in DCM (20 mL), TFA (16.7 mL, 218 mmol) was added and
the mixture was stirred at rt for 1 h. The solvent was concentrated
off. The crude residue was diluted with H.sub.2O (30 mL), taken up
to pH 12 with 10% aqueous NaOH solution and extracted with DCM (30
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated to give the title compound as brown oil
(1.66 g, quant yield).
HPLC-MS (Method A): Ret, 1.01 min; ESI+-MS m/z, 191 (M+1).
Intermediate 4A. tert-Butyl
2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethylcarbamate
##STR00073##
tert-Butyl 2-bromoethylcarbamate (0.71 g, 3.15 mmol) was added to a
solution of N-benzyl-N-methylpyrrolidin-3-amine (INT 3, 0.4 g, 2.1
mmol) and DIPEA (0.73 mL, 4.2 mmol) in ACN (15 mL). The reaction
mixture was stirred at 60.degree. C. overnight and then it was
cooled down to rt. The solvent was concentrated in vacuo and the
residue was partitioned between AcOEt and sat aqueous NaHCO.sub.3
solution. The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product thus
obtained was purified by flash chromatography on silica gel,
gradient DCM:MeOH from (100:0) to (70:30) to give the title
compound (0.42 g, 60% yield).
HPLC-MS (Method A): Ret, 1.84 min; ESI+-MS m/z, 334 (M+1).
This method was used for the preparation of intermediates 4B-4E
using suitable starting materials:
TABLE-US-00003 Ret MS INT Structure Chemical name Method (min) (M +
H) 4B ##STR00074## tert-butyl (2-(5- benzylhexahydro-
pyrrolo[3,4-c]pyrrol- 2(1H)- yl)ethyl)carbamate B 1.89 346 4C
##STR00075## tert-butyl (2-(3- (benzyl(methyl) (amino)azetidin-1-
yl)ethyl)carbamate A 1.75 320 4D ##STR00076## tert-butyl (2-(3-
(isobutyl(methyl) amino)azetidin-1- yl)ethyl)carbamate A 1.75 286
4E ##STR00077## tert-butyl (2-(3- ((2- methoxyethyl)(methyl)
amino)azetidin-1- yl)ethyl)carbamate A 1.36 302
Intermediate 5A.
1-(2-Aminoethyl)-N-benzyl-N-methylpyrrolidin-3-amine
##STR00078##
Over a suspension of tert-butyl
2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethylcarbamate (INT 4A,
0.42 g, 1.26 mmol) in DCM (6 mL), TFA (2.36 mL, 30.86 mmol) was
added and the mixture was stirred at rt for 4 h. The solvent was
concentrated off. The crude residue was diluted with H.sub.2O (5
mL), taken up to pH 12 with 10% aqueous NaOH solution and extracted
with DCM (10 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the title
compound as oil (0.26 g, yield 90%).
HPLC-MS (Method A): Ret, 1.12 min; ESI+-MS m/z, 234 (M+1).
This method was used for the preparation of intermediates 5B-5E
using intermediates 4B-4E as starting materials:
TABLE-US-00004 Ret MS INT Structure Chemical name Method (min) (M +
H) 5B ##STR00079## 2-(5- benzylhexahydro- pyrrolo[3,4-c]pyrrol-
2(1H)- yl)ethanamine A 1.17 246 5C ##STR00080## 1-(2-
aminoethyl)-N- benzyl-N- methylazetidin-3- amine A 1.10 220 5D
##STR00081## 1-(2- aminoethyl)-N- isobutyl-N- methylazetidin-3-
amine A 1.02 186 5E ##STR00082## 1-(2- aminoethyl)-N-(2-
methoxyethyl)-N- methylazetidin-3- amine A 0.77 202
Intermediate 6A.
N-(2-(3-(Benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-3-fluoropyridin-2-ami-
ne
##STR00083##
1-(2-Aminoethyl)-N-benzyl-N-methylpyrrolidin-3-amine (INT 5A, 0.17
g, 0.73 mmol), Pd.sub.2(dba).sub.3 (0.067 g, 0.07 mmol),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 0.055 g, 0.087
mmol) and .sup.tBuOK (0.210 g, 2.19 mmol) were added to a Raddley
tube, under nitrogen, and dissolved in anhydrous THF (15 mL).
2-Bromo-3-fluoropyridine (0.135 g, 0.76 mmol) was added and the
reaction mixture was stirred at 55.degree. C. overnight. The
solvents were evaporated and the residue was dissolved in EtOAc and
aqueous sat NaHCO.sub.3 solution. The aqueous layer was extracted
with EtOAc and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product thus
obtained was purified by flash chromatography on neutral alumina,
gradient CH:AcOEt from (100:0) to (80:20) to give the title
compound as a solid (0.08 g, 34% yield).
HPLC-MS (Method A): Ret, 1.76 min; ESI+-MS m/z, 329 (M+1).
This method was used for the preparation of intermediates 6B-6G
using suitable starting materials:
TABLE-US-00005 Ret MS INT Structure Chemical name Method (min) (M +
H) 6B ##STR00084## N-benzyl-N- methyl-1-(2- (phenylamino)ethyl)
pyrrolidin-3- amine A 2.05 310 6C ##STR00085## N-(2-(3-
(benzyl(methyl) amino)pyrrolidin-1- yl)ethyl)-6- (trifluoromethyl)
pyridin-2-amine A 2.21 379 6D ##STR00086## N-(2-(5-
benzylhexahydro- pyrrolo[3,4-c]pyrrol- 2(1H)-yl)ethyl)-6-
(trifluoromethyl) pyridin-2-amine A 2.21 391 6E ##STR00087##
N-(2-(3- (benzyl(methyl) amino)azetidin-1- yl)ethyl)-6-
(trifluoromethyl) pyridin-2-amine A 2.07 365 6F ##STR00088##
N-(2-(3- (isobutyl(methyl) amino)azetidin-1- yl)ethyl)-6-
(trifluoromethyl) pyridin-2-amine A 2.11 331 6G ##STR00089##
N-(2-(3-((2- methoxyethyl)(methyl) amino)azetidin- 1-yl)ethyl)-6-
(trifluoromethyl) pyridin-2-amine A 1.67 347
Example 1.
N-(2-(3-(Benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(3-fluoro-
pyridin-2-yl)propionamide
##STR00090##
Propionyl chloride (78.5 .mu.L, 0.616 mmol) was added to a solution
of
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-3-fluoropyridin-2-ami-
ne (INT 6A, 0.08 g, 0.205 mmol) and
N-ethyl-N-isopropylpropan-2-amine (104.6 .mu.L, 0.82 mmol) in DCE
(10 mL) in a process vial under nitrogen atmosphere. The reaction
mixture was heated under microwave irradiating conditions for 60
min at 80.degree. C., after which it was allowed to reach rt. The
reaction mixture was diluted with DCM (10 mL) and water (10 mL) was
added. The aqueous phase was acidified with 10% HCl and the phases
were separated. The organic phase was extracted with 10% HCl and
the aqueous phase was made alkaline with 20% NaOH while cooling.
AcOEt (10 mL) was added, the phases were separated and the aqueous
phase was extracted with AcOEt. The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and concentrated to give the
title compound (0.076 g, yield 96%).
HPLC-MS (Method A): Ret, 1.74 min; ESI+-MS m/z, 385 (M+1).
This method was used for the preparation of example 2 using
suitable starting materials:
TABLE-US-00006 Ret MS EX Structure Chemical name Method (min) (M +
H) 2 ##STR00091## N-(2-(3- (benzyl(methyl)amino) pyrrolidin-1-
yl)ethyl)-N- phenylpropionamide A 2.01 366
The two enantiomers of example 2 were separated by Chiralpak IC
column, flow rate 11 mL/min A: n-Heptane; B: (EtOH+0.33% DEA)
90/10, rt to give examples 3 and 4.
Example 5.
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifl-
uoromethyl)pyridin-2-yl)propionamide
##STR00092##
Propionyl chloride (259 .mu.L, 2.97 mmol) was added to a solution
of
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-6-(trifluoromethyl)py-
ridin-2-amine (INT 6B, 375 mg, 0.99 mmol) and
N-ethyl-N-isopropylpropan-2-amine (690 .mu.L, 3.96 mmol) in toluene
(35 mL). The reaction mixture was stirred for 5 h at 85.degree. C.,
after which it was allowed to reach rt. The reaction mixture was
diluted with DCM (10 mL) and HCl 2N (10 mL) was added and the
phases were separated. The organic phase was extracted with 2 N HCl
and the aqueous phase was made alkaline with 20% aqueous NaOH
solution, while cooling. AcOEt was added, the phases were separated
and the aqueous phase was extracted with AcOEt. The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the title compound (340 mg, yield 79%).
HPLC-MS (Method A): Ret, 2.18 min; ESI+-MS m/z, 435 (M+1).
The two enantiomers of example 5 were separated by Chiralpak IC
column, flow rate 11 mL/min A: n-Heptane; B: (EtOH+0.33% DEA)
90/10, rt to give examples 6 and 7.
This acylacion method was used for the preparation of example 8,
using INT 6D as starting material.
TABLE-US-00007 Ret MS EX Structure Chemical name Method (min) (M +
H) 8 ##STR00093## N-(2-(5- benzylhexahydro- pyrrolo[3,4-
c]pyrrol-2(1H)- yl)ethyl)-N-(6- (trifluoromethyl) pyridin-2-
yl)propionamide A 2.18 448
Example 9.
N-(2-(3-(benzyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluo-
romethyl)pyridin-2-yl)propionamide
##STR00094##
Propanoic anhydride (178 .mu.L, 1.45 mmol) was added to a solution
of
N-(2-(3-(benzyl(methyl)amino)azetidin-1-yl)ethyl)-6-(trifluoromethyl)pyri-
din-2-amine (INT 6E, 176 mg, 0.48 mmol) in pyridine (7 mL) at
0.degree. C. The reaction mixture was allowed to reach rt and
stirred overnight. Then, volatiles were removed under vacuum and
the crude was extracted in EtOAc washing with sat aqueous
NaHCO.sub.3 solution. The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product thus
obtained was purified by flash chromatography on silica, gradient
DCM/MeOH from (100:0) to (85:15) to give the title compound (80 mg,
39% yield).
HPLC-MS (Method A): Ret, 2.06 min; ESI+-MS m/z, 421 (M+1).
This acylacion method was used for the preparation of examples
10-11, using INT 6F and 6G as starting materials.
TABLE-US-00008 Ret MS EX Structure Chemical name Method (min) (M +
H) 10 ##STR00095## N-(2-(3- (isobutyl(methyl) amino)azetidin-
1-yl)ethyl)-N-(6- (trifluoromethyl) pyridin-2- yl)propionamide A
2.1 388 11 ##STR00096## N-(2-(3-((2- methoxyethyl) methyl)amino)
azetidin-1-yl)ethyl)- N-(6- (trifluoromethyl) pyridin-2-
yl)propionamide A 1.66 404
Example 12.
N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluorometh-
yl)pyridin-2-yl)propionamide
##STR00097##
a)
N-(2-(3-(methylamino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyrid-
in-2-yl)propionamide
N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl-
)pyridin-2-yl)propionamide (Example 5, 270 mg, 0.62 mmol) was
dissolved in MeOH (20 mL) and ammonium formate (176 mg, 2.80 mmol)
and Pd (55 mg, 20% Wt) was added. The suspension was stirred under
N.sub.2 atmosphere for 3 h at 65.degree. C. The reaction mixture
was filtered through celite, washed with MeOH and concentrated, to
give the title compound (186 mg, yield 87%).
HPLC-MS (Method A): Ret, 1.31 min; ESI.sup.+-MS m/z, 345 (M+1).
b) Title Compound
1-Bromo-2-methylpropane (125 .mu.L, 1.15 mmol) was added to a
solution the compound obtained in the previous step (99 mg, 0.28
mmol) and K.sub.2CO.sub.3 (119 mg, 0.86 mmol) in ACN (12 mL). The
reaction mixture was stirred at 70.degree. C. for 48 h and then it
was cooled down to rt. AcOEt and sat aqueous NaHCO.sub.3 solution
were added and the phases were separated. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated to give the
title compound (66 mg, yield 57%).
HPLC-MS (Method A): Ret, 2.06 min; ESI+-MS m/z, 401 (M+1).
The two enantiomers of example 12 were separated by Chiralpak IC
column, flow rate 11 mL/min A: n-Heptane; B: (EtOH+0.33% DEA)
90/10, rt to give examples 13 and 14.
This method and the subsequent chiral HPLC separation was used for
the preparation of example 15 and its corresponding enantiomers
examples 16 and 17
TABLE-US-00009 Ret MS EX Structure Chemical name Method (min) (M +
H) 15 ##STR00098## N-(2-(3-((2- ethoxyethyl)(methyl)
amino)pyrrolidin- 1-yl)ethyl)-N-(6- (trifluoromethyl) pyridin-2-
yl)propionamide A 3.58 418
Example 18.
N-(2-(5-isobutylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-N-(6-(trifl-
uoromethyl)pyridin-2-yl)propionamide
##STR00099##
a)N-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-N-(6-(trifluoromethy-
l)pyridin-2-yl)propionamide
N-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-N-(6-(trifluo-
romethyl)pyridin-2-yl)propionamide (Example 8, 760 mg, 1.7 mmol)
was dissolved in DCE (10 mL) and chloroethyl chloroformate (487 mg,
3.4 mmol) was added. The mixture was stirred for 16 h at 85.degree.
C. Then, volatiles were removed under vacuum and MeOH (8 mL) was
added and stirred at the reflux temperature for 2 h. The crude
mixture was concentrated to give the title compound (174 mg, yield
51%), that was used in the next step without further
purification.
HPLC-MS (Method A): Ret, 1.36 min; ESI+-MS m/z, 357 (M+1).
b) Title Compound
The title compound was obtained following the method described for
example 8 step b.
HPLC-MS (Method A): Ret, 1.99 min; ESI+-MS m/z, 414 (M+1).
This method was used for the preparation of example 19:
TABLE-US-00010 Ret MS EX Structure Chemical name Method (min) (M +
H) 19 ##STR00100## N-(2-(5-(2- ethoxyethyl) hexahydropyrrolo
[3,4-c]pyrrol-2(1H)- yl)ethyl)-N-(6- (trifluoromethyl) pyridin-2-
yl)propionamide A 1.76 430
Table of Examples with Binding to the .mu.-Opioid Receptor and the
.sigma..sub.1-Receptor:
Biological Activity
Pharmacological Study
Human .sigma..sub.1 Receptor Radioligand Assay
To investigate binding properties of test compounds to human
.sigma..sub.1 receptor, transfected HEK-293 membranes and
[.sup.3H](+)-pentazocine (Perkin Elmer, NET-1056), as the
radioligand, were used. The assay was carried out with 7 .mu.g of
membrane suspension, 5 nM of [.sup.3H](+)-pentazocine in either
absence or presence of either buffer or 10 .mu.M Haloperidol for
total and non-specific binding, respectively. Binding buffer
contained Tris-HCl 50 mM at pH 8. Plates were incubated at
37.degree. C. for 120 minutes. After the incubation period, the
reaction mix was then transferred to MultiScreen HTS, FC plates
(Millipore), filtered and plates were washed 3 times with ice-cold
10 mM Tris-HCL (pH7.4). Filters were dried and counted at
approximately 40% efficiency in a MicroBeta scintillation counter
(Perkin-Elmer) using EcoScint liquid scintillation cocktail
Human .mu.-Opioid Receptor Radioligand Assay
To investigate binding properties of test compounds to human
.mu.-opioid receptor, transfected CHO-K1 cell membranes and
[.sup.3H]-DAMGO (Perkin Elmer, ES-542-C), as the radioligand, were
used. The assay was carried out with 20 .mu.g of membrane
suspension, 1 nM of [.sup.3H]-DAMGO in either absence or presence
of either buffer or 10 .mu.M Naloxone for total and non-specific
binding, respectively. Binding buffer contained Tris-HCl 50 mM,
MgCl2 5 mM at pH 7.4. Plates were incubated at 27.degree. C. for 60
minutes. After the incubation period, the reaction mix was then
transferred to MultiScreen HTS, FC plates (Millipore), filtered and
plates were washed 3 times with ice-cold 10 mM Tris-HCL (pH 7.4).
Filters were dried and counted at approximately 40% efficiency in a
MicroBeta scintillation counter (Perkin-Elmer) using EcoScint
liquid scintillation cocktail.
Results:
As this invention is aimed at providing a compound or a chemically
related series of compounds which act as dual ligands of the
.sigma..sub.1 receptor and the .mu.-opioid receptor it is a very
preferred embodiment in which the compounds are selected which act
as dual ligands of the .sigma..sub.1 receptor and the .mu.-opioid
receptor and especially compounds which have a binding expressed as
K.sub.i which is preferably <1000 nM for both receptors, more
preferably <500 nM, even more preferably <100 nM.
The following scale as been adopted for representing the binding to
the the .sigma..sub.1 receptor and the .mu.-opioid receptor
expressed as K.sub.i: + Both K.sub.i-.mu. and
K.sub.i-.sigma..sub.1>=500 nM ++ One K.sub.i<500 nM while the
other K.sub.i is >=500 nM +++ Both K.sub.i-.mu. and
K.sub.i-.sigma..sub.1<500 nM ++++ Both K.sub.i-.mu. and
K.sub.1-.sigma..sub.1<100 nM
All compounds prepared in the present application exhibit binding
to the .sigma..sub.1 receptor and the .mu.-opioid receptor, in
particular the following binding results are shown:
TABLE-US-00011 .mu. and .sigma..sub.1 dual EX binding 1 ++ 2 +++ 3
++ 4 +++ 5 + 6 ++ 7 +++ 8 ++ 9 ++ 10 ++ 11 + 12 + 13 + 14 + 15 + 16
+ 17 + 18 ++ 19 ++
* * * * *